SYNAPSE 9~251-301 (1991)

Clinical and Biochemical Aspects of Depressive Disorders: 11. Transmitter/ -

Receptor Theories SALLY CALDECOTT-HAZARD,DAVID G. MORGAN, FRANK DELEON-JONES, DAVID H. OVERSTREET, AND DAVID JANOWSKY Laboratory of Biomedical and Environmental Science, University of California at Los Angeles, Los Angeles, California 90024 (S.C.-H.);Department of Gerontology, University of Southern California, Los Angeles, California 90089 (D.G.M.);Psychiatry Department, Olive View Medical Center, Sylmar, California 91342 (F.D.-J.);Center for Alcohol Studies, University of North Carolina at Chapel Hill, Medical School Building, Chapel Hill, North Carolina 27599 (D.H.O., D.J.)

KEY WORDS

Depressive disorders, Neurotransmitters, Receptors

The present document is the second of three parts in a review that focuses ABSTRACT on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptorltransmitter theories of depressive disorders are discussed in this section. Specifically,data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic, and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part I11 of this review, discusses treatments for depression and some of the controversies in this field. INTRODUCTION Although many data have recently accumulated on the biological and biochemical basis of depressive disorders and treatments, data from clinical and animal studies are not often integrated into a single document. The present review fulfills this goal, with the intent of producing a more comprehensive understanding, by neurobiologists and physicians, of the current issues in depressive disorders. The present report is the second of three parts of the review, which include classification schemes and techniques for studying depressive disorder (Part I), transmittedreceptor theories of depression (Part 11)) and depression treatments and controversial issues (Part 111).The transmitter/receptor theories discussed include those relating to noradrenergic, serotonergic, cholinergic, dopaminergic, GABA ergic, and peptidergic (i.e., corticotropin-releasing hormone and opioid peptide) mechanisms underlying depression. Also, each of the subsections on these transmitters includes discussions on the pharmacology of these systems, biochemical measures in humans and animal models, and the effects of antidepressants on the neurochemistry of humans and animals. Interactions between the noradrenergic and serotonergic systems and the noradrenergic and cholinergic systems are also described. Although the terms mood disorder, affectivedisorder, 0 1991 WILEY-LISS, INC.

and depressive disorder are not technically identical, these terms are used interchangeably in the present review, to facilitate integration of information from different sources. Three tables summarize abbreviations (Table I), neurotransmitter, and metabolite changes in depressed patients (Table 11), and antidepressant effects on neurotransmitters, metabolites, and receptors (Table 111)described in the various sections of this document. NOREPINEPHRINE (F. DeLeon-Jones) During the past three decades, our understanding of the mechanisms involved in the pathogenesis of the affective disorders has increased considerably. Investigations in the field of behavioral neuropsychopharmacology in animals, and clinical studies of humans with affective disorders, have provided relevant information as to pre- and postsynaptic mechanisms implicated in the manifestation of these disorders. Since the discovery of the tricyclic antidepressant drugs during the 1950s) many investigations have supported a significant role for the biogenic amines, particularly norepinephrine (NE) and serotonin (5-HT) (Zeller and Barsky, 1952; Received April 12,1991; accepted in revised form April 24,1991. Address reprint requests to Dr. Sally Caldecott, 3385 South US. Highway 17-92, Suite 210/0, Casselberry,FL 32707.

252

S. CALDECOTT-HAZARD ET AL. TABLE I. Abbreviations used

Ach ACTH ADT AMPT Bmax B-MSH C CAMP CNS CoA COMT CRF CRH CSF DA DHA 5-DHT DOMA DOPA DOPAC DOPEG ECT Epi FRL FSL GABA GABA-T GAD GDP GTP 5-HIAA HPA 5-HT 5-HTP HVA Kd Km

Acetylcholine corticotropin, adrenocorticotropic hormone antidepressant therapy Alpha-methyl-p-tyrosine maximum number of binding sites for a radioligand B-Melanocyte stimulating hormone catalytic moiety of adenylate cyclase cyclic adenosine monophosphate central nervous system coenzyme A catechol-O-methyltransferase corticotropin-releasingfactor (same as CRH) corticotropin-releasinghormone (same as CRF) cerebrospinal fluid dopamine dihydroalprenolol 5, 7-dihydroxytryptamine 3, 4-dihydroxymandelic acid 3.4-dihydroxyphen ylalanine 3.4-dihydroxyphenylaceticacid 3.4-dih ydroxyphenylglycol

and Axelrod, 1964). Studies during the 1980s have decisively refined this earlier hypothesis by recognizing a role for receptors, particularly pre- and postsynaptic adrenoreceptors, in affective disorders. This section reviews and summarizes evidence supporting three hypotheses of noradrenergic involvement in depression: the hypothesis of noradrenergic involvement in depression: the hypothesis of neurotransmitter availability, that of receptor changes, and that of changes in secondary messenger systems. The reader should keep in mind that it is not clear whether treatment with antidepressants increases or decreases neurotransmission at noradrenergic synapses. In experimental animals, the net effect of these opposing influences is uncertain (Charney et al., 1981) and, in man, it is quite unknown.

Pharmacology of the noradrenergic system The primary pathway in the formation of norepinephrine (noradrenaline)within neurons involvesthree enzymatic steps: (1)the amino acid tyrosine is first converted to 3,4-dihydroxyphenylalanine(DOPA) by the enzyme tyrosine hydroxylase; (2) DOPA is then converted to dopamine by aromatic amino acid decarboxylase (DOPA-decarboxylase); and (3) dopamine is transformed to norepinephrine by dopamine-Betahydroxylase. Tyrosine hydroxylase is the rate-limiting step for these reactions (i.e., the rate at which norepinephrine is produced is controlled by the amount of this enzyme present and the speed with which it acts). LC Interestingly, the rate of synthesis and turnover of mAChR brain norepinephrine is lower than for the neurotransMA0 MA01 mitters dopamine or serotonin. This may explain why MET noradrenergic neurons show substantial depletions of MHPG 3-methoxy-4-h ydrox yphenethyleneglycol messenger ribonucleic acid mRNA transmitter after relatively short periods of sustained 3-methoxytyramine MTA physiological activity (Cooper et al., 1986). guanine nucleotide-binding protein N Norepinephrine (NE) is inactivated via two enzyme norepinephrine NE inhibitory guanine nucleotide-binding protein Ni pathways. Much of the NE released by nerve terminals normetanephrine NM is thought to be taken up by the same presynaptic stimulatory guanine nucleotide-bindingprotein Ns terminals. Intraneuronal monoamine oxidase (MAO), p-chlorophenylalanine pCPA phosphoinositide PI an enzyme localized predominantly on the outer mempro-opiomelanocortin POMC brane of the mitochondria, converts NE to its correneurotransmitter receptor R sponding aldehyde. In the central nervous system rapid eye movement REM serotonin uptake blockers SUBS (CNS), the aldehyde is largely converted to 3,4-diydroxtricyclic antidepressants TCAs yphenylglycol (DOPEG) by aldehyde reductase, and Vanillylmandelic acid, 3-methoxy-4-hydroxymandelicacid VMA DOPEG is transformed to 3-methoxy-4-hydroxyphenmaximal rate of enzymatic activity under ideal Vmax conditions ethyleneglycol (MHPG) by catechol-O-methyltransferase VTA ventral teemental area of the brain (COMT) (Cooper et al., 1986). MHPG can be measured in the cerebrospinal fluid (CSF); some MHPG also moves into the plasma (and perhaps urine). In the Sjoerdsma et al., 1955; Brodie et al., 1955; Brodie et al., peripheral nervous system, the aldehyde of NE is pri1959; Carlson et al., 1957; Shore and Brodie, 1957; marily converted to 3,4-dihydroxymandelic acid Shore et al., 1955) in the etiopathogenesis of the affec- (DOMA) by aldehyde dehydrogenase, then to 3-methtive disorders. These investigations suggested the hy- oxy-4-hydroxymandelic acid (also known as vanillylpothesis that tricyclic antidepressants, through the mandelic acid, VMA) by COMT. blockade of neurotransmitter reuptake, increased neuThe second pathway for the inactivation of released rotransmissions at noradrenergic synapses (Glowinski NE probably exists extraneuronally. The enzyme electroconvulsive shock therapy epinephrine Flinders resistant line of rats Flinders sensitive line of rats gamma-aminobutyric acid Gamma-aminobutyric acid transaminase glutamic acid decarboxylase guanosine 5’-diphosphate guanosine 5’-triphosphate 5-hydroxyindoleacetic acid hypothalamic-pituitary-adrenal 5-hydroxytryptamine, serotonin 5-hydroxytryptophan homovanillic acid equilibrium dissociation constant for a radioligand concentration of a substrate producing one-half the V,, activity locus coeruleus muscarinic acetylcholine receptors monoamine oxidase monoamine oxidase inhibitor metanephrine

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DEPRESSION: CLINICAL AND BIOCHEMICAL ASPECTS TABLE II. Summary of frequently reported neurotransmitter and metabolite changes in some subgroups of depressed patients (compared with normal controls)'

NE

MHPG

NM

VMA

Epi

MET

CSF

nd

1 t

nd

nd

nd

nd

nd

Plasma

nd

nd

nd

nd

nd

nd

nd

Uptake into platelets Urine

nd

nd

nd

nd

nd

nd

t

1

-

1

Brain tissue

nd

nd

- nd- nd- ndnd 1

t

t

t

DA

HVA

5-HT

5-HIAA

GABA

GAD

CRH

1 t psychotic

nd

1

nd

t

dep. nd

-

1

Endorphins

1

nd

1

nd

nd

-

nd

nd

1

nd

nd

nd

nd

nd

tmania

nd

nd

nd

nd

nd

nd

nd

nd

nd

1

1

nd

1

nd

nd

tmania -dep. 1

I

'nd, no data in this review; 1, increased levels as compared with controls; I,decreased levels as compared with controls; -, no change as compared to controls. NE, norepinephrine; MHPG, 3-methoxy-4-hydroxyphenethyleneglycol; NM, normetanephrine; VMA, 5methoxy4hydroxymandelic acid; Epi, epinephrine; MET, metanephrine; DA, dopamine; HVA, homovanillic acid; 5-HT. serotonin; 5-HIAA, 5-hydroxy-indoleaceticacid; GABA, Gamma-aminobutyric acid; GAD, glutamatic acid decarboxylase; CRH, corticotropin-releasing hormone.

COMT converts NE to normetanephrine (NM); then MA0 (probably extraneuronal) transforms NM to an intermediate aldehyde. That aldehyde is converted by aldehyde dehydrogenase t o VMA. It is notable that, while VMA is readily detected in the urine, very little, if any, is found in the brain (Cooper et al., 1986). Noradrenergic receptors are divided into two categories: autoreceptors (receptors on the soma, dendrites, or presynaptic terminals of the same neuron that releases the NE; these receptors respond to the neuron's own transmitter); and postsynaptic receptors (receptors on a postsynaptic neuron that respond to the NE released by the presynaptic neuron). One type of autoreceptor has been labeled an Alpha-2 receptor (A-2). However, A-2 receptors are also thought to be located postsynaptically. In a number of tissue preparations, A-2 receptor function has been linked to the inhibition of adenylate cyclase activity, causing a decrease in the second messenger cyclic adenosine monophosphate (cyclic AMP) (Janowsky and Sulser, 1987). The other types of postsynaptic receptors are the Alpha-1 (A-11, Beta-1 (B-l), and Beta-2 (B-2) receptors. A-1 receptors are thought t o be linked t o the production of the second messengers inositol trisphosphate and 1,2-diacylglycerol. Both types of beta receptors are thought to stimulate the production of cyclicAMP (Janowsky and Sulser, 1987).

tionally increases the concentration of neurotransmitter at the synapse, a reduction in this transmitter was postulated to be a determining factor in the appearance of depression. The original catecholamine hypothesis of the affective disorders was formulated by Schildkraut (1965). It proposed that depression is related to a functional deficiencyof neurotransmitters at important central adrenergic receptor sites, whereas mania is associated with a functional excess of these transmitters. The evidence in support of this theory has been reviewed by prominent investigators over the years (Schildkraut, 1965; Schildkraut and Kety, 1967; Baldessarini, 1975; Waldmeir, 1965). A brief review of this evidence will follow as a basis for a discussion of the current hypotheses and investigations in this field.

Norepinephrine deficiency in depressiodexcess in mania Approximately 25 years ago, observations were made that reserpine tended to cause depression among hypertensive patients (Bunney and Davis, 1965) and that reserpine depleted intraneuronal stores of catecholamines and indolamines (Kopin, 1965). Subsequent animal experiments showed that a norepinephrine precursor that crosses the brain blood barrier, dihydroxyphenylalanine, reversed the sedation produced by reserpine in animals (Schildkraut, 1965), While these observations suggested that the reserpine-induced synBiochemical measures in humans and animal drome in animals could be a model for human depresmodels (neurotransmitter availability) sion, other work questioned the applicability of this The most generally accepted theory of antidepressant animal model to humans (Mendels and Frazer, 1974). Early work with imipramine showed that this comaction has been that these drugs enhance neurotransmission through relative increases of monoamine levels pound potentiates the responses to sympathetic nerve at synapticjunctions in the brain. For example, tricyclic stimulation and to the administration of exogenous antidepressants have been reported to prevent the prin- norepinephrine in animals and man (Glowinski and cipal means of physiological inactivation of norepineph- Axelrod, 1964; Klerman and Cole, 1965; Prien et al., rine, i.e., its reuptake into nerve terminals (Glowinski 1973). It was also found that the tricyclic antidepresand Axelrod, 1964). Since a blockade of reuptake func- sants, imipramine, desmethylimipramine, and nortrip-

S. CALDECOTT-HAZARDET AL.

254

TABLE III. Summary of antidepressant-induced changes in neurotransmitters, metabolites. and their receDtors in humans and animals' Drugs What was measured Concentrations in brain tissue MHPG Enkephalins Concentrations in CSF MHPG HVA 5-HIAA Beta-Endorphin Concentrations in urine MHPG Effects on uptake of NE 5-HT GABA Number of receptors Brain Alpha-:! Platelet Alpha-2 Brain Alpha-I Brain Beta Brain 5-HT-2 Brain 5-HT-1 Brain mACh Brain Dopamine-1 Brain GABAp Brain mu and delta opioid Sensitivity of somatodendritic DA receptors Effect on stimulation of CAMP by NE Effect on stimulation of PI by muscarinic agonists Amount of glucocorticoid mRNA or receptor sites in brain

Tricyclics

MAOIs

SUBS

Iprindole

LI

ECT

t 1

nd nd

nd nd

nd

nd nd

nd

t

I

1

nd

1

1 1 1

nd

nd

nd

nd nd nd nd

nd nd nd nd

nd nd nd t

It-

nd

nd

nd

nd

nd

I I

nd nd nd

1

--

nd

nd

nd nd nd

nd nd nd

nd nd nd

nd nd nd

nd nd nd

nd

nd nd nd

I

l-

I

1

1 1

It-

1

1-

1 1 t-

nd nd

nd

nd

nd nd t nd

nd nd nd nd nd

1-

1

nd

1

1

nd 11

nd

1

Itnd tI I

1

I t nd nd nd t-

t

1 t

nd nd

I

nd nd nd

tl

nd

nd

I

1

1

nd

1

nd

nd

nd

1-

nd

nd

nd

nd

nd

nd

t

1

'nd, no data in this review; 1, increased; I,decreased;-, no change. Arrows represent the most frequently observed (not necessarily all) effects of the drugs in each group.MAOI, monoamine oxidase inhibitor;SUB, serotonin uptakeblocker;LI, lithium; ECT, electroconvulsive therapy; CSF, cerebrospinal fluid; MHPG, 3-methoxy-4-hydroxyphenethyleneglycol; HVA, homovanillic acid; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; NE, norepinephrine;DA, dopamine; GABA, Gammaaminobutyric acid; mACh, muscarinic cholinergic; CAMP,cyclic adenosine monophosphate;PI, phosphoinositide; mRNA, messenger ribonucleic acid.

tyline, but not amitriptyline, blocked the uptake of isotropically labelled norepinephrine injected into the lateral ventricle of the rat (Schildkraut et al., 1969; Lidbrink et al., 1971). Finally, mouse slices of cerebral cortex, incubated with imipramine, showed a blockade of NE and 5-HT uptake. Desmethylimipramine was found to be 10 times more potent than imipramine a t blocking NE uptake, but 10 times less potent than imipramine at blocking 5HT uptake (Ross and Renyi, 1967). These initial pharmacological findings in animals prompted exploration of other animal models of depression. For example, changes in adrenergic systems of the brain were reported to play a significant part in produc-

ing or mediating stress-induced behavioral depression (Weiss et al., 1970). Specifically, the concentration of norepinephrine within the locus coeruleus (LC) was reduced by exposure to uncontrollable shock in rodents, and that stress-induced behavioral depression correlated with lower levels of norepinephrine in LC (Weiss et al., 1981). The hypothesis that life events and neurobiological changes, alone or in combination, could precipitate depression has been explored in rhesus monkeys. Maternally deprived peer-reared monkeys are very sensitive to the depressive effects of alpha-methyl-p-tyrosine (AMP"), a tyrosine hydroxylase inhibitor that depletes CNS NE and dopamine (DA). By contrast, mother/

DEPRESSION: CLINICAL AND BIOCHEMICAL ASPECTS

peer-reared monkeys are relatively resistant to AMP" challenge (Kraemer and McKinney, 1979). Also, changes in behavioral response to separation were associated with changes in CSF levels of NE. Increased despair was associated with lowered CSF norepinephrine, and ameliorated despair was associated with increased CSF NE (Kraemer et al., 1984). Evidence also exists for alterations in catecholamines and their metabolites in human subjects with affective disorders (Table 11).Urinary norepinephrine and one of its metabolites, normetanephrine (NM) have been reported to be altered in patients with manic-depressive illness. Strom-Olsen and Weil-Malherbe (1958) found that urinary excretion of norepinephrine and epinephrine (Epi) was greater during the manic, as compared to depressed, phase in patients with manic-depressive disorders. Bjorum et al. (1972) reported elevated excretion of NE and Epi in a series of manic patients, whereas no significant changes in the excretion of either amine were observed in patients with endogenous depressions (retarded depressions were not separately characterized). Shinfuku et al. (1961) reported increases in the urinary excretion of NE during mania in a single patient with regular manic-depressive mood changes. Greenspan et al. (1969) found that excretion of NE and NM was greater during hypomania than during normothymic periods or during periods of retarded depression. In a longitudinal study of depressed patients, Schildkraut et al. (1965) observed a gradual rise in NM excretion during the period of definitive clinical improvement in depressed patients treated with imipramine. Bunney et al. (1972)measured urinary catecholamines daily in a group of patients. Norepinephrine and DA were elevated before and during the manic episode. In particular, NE was significantly increased 1 day before the shift from depression to mania. MHPG, another catecholamine metabolite, was discovered by Axelrod and associates in 1959 (Axelrod et al., 1959). Subsequent reports have shown that MHPG is the major metabolite of brain NE (Glowinski et al., 1965; Maas and Landis, 1968; Mannarino et al., 1963; Schanberg et al., 1968; Sharman, 1969). In addition, it has been shown that either stress or direct stimulation of the locus coeruleus produces an increased turnover of NE and an increase in the sulfate conjugate ofMHPG in the rat cerebrum and that these effects are abolished by ablation of the locus coeruleus. Thus, MHPG in the brain may reflect the functional activity of central noradrenergic neurons (Korf et al., 1973a,b). There is also evidence suggesting that a certain fraction of urinary MHPG has its origins in the metabolism of NE within the brain, whereas urinary norepinephrine (NE), normetanephrine (NM),metanephrine (MET),and perhaps methoxy-4-hydroxymandelicacid (VMA) originate in pools of catecholamines outside the CNS (Glowinski et al., 1965; Maas and Landis, 1968; Maas et al., 1973, 1979).

255

It should be noted, however, that although there is general agreement that MHPG is the major metabolite of brain NE, definitive information is not available as to the precise amount of MHPG excreted in urine derived from the brain. Furthermore, recent studies suggest that the urinary excretion rates of these metabolites may be independent of compartments such as CNS and periphery (Linnoila et al., 1986). Still, assaying urinary MHPG, along with other catecholamine metabolites, has been considered a reasonable strategy for clinical studies of the catecholamine hypothesis of affective disorders. Using this approach, Maas et al. (1968) found that a diagnostically heterogeneous group of hospitalized depressed patients excreted significantly less MHPG than did healthy subjects, although urinary NM and MET levels for the two groups were the same. Subsequently, Greenspan et al. (19691,Bond et al. (19711, and DeLeonJones et al. (1973) published data indicating that bipolar patients excreted significantly less MHPG during periods of euthymia or mania. Moreover, Schildkraut et al. (1973) showed that patients with a bipolar depressive disorder represent a clinically identifiable subgroup of depressed patients who excrete less than normal quantities of MHPG. Thus, there seems to be agreement among separate groups of researchers that some depressed patients excrete less than normal quantities of MHPG. By contrast, the data presented in the initial report by Maas et al. (19681, as well as in other reports (Dekirmenjian et al., 1971; Schildkraut et al., 1973), indicate that not every depressed patient excretes less than normal quantities of urinary MHPG. Also, patients who excrete less MHPG can be identified by their behavioral responses to the antidepressants desmethylimipramine or imipramine. Specifically, a low pretreatment urinary MHPG predicts a favorable response to desmethylimipramine or imipramine, but pretreatment values of NM, MET, or VMA are not significantly related to treatment response (Maas et al., 1972). Fawcett et al. (1972) showed that patients who excrete less than normal quantities of MHPG respond with an elevation of mood when given d-amphetamine, whereas patients who excrete normal or greater than normal quantities of MHPG either do not respond or respond with a worsening mood when given d-amphetamine (Fawcett et al., 1972). Schildkraut (1973) found that patients who excrete normal or greater than normal quantities of MHPG responded best to amitriptyline. The findings of Maas et al. (19681, Fawcett et al. (1972), and Schildkraut (1973) were confirmed by a report of Beckmann and Goodwin (1975).These investigators measured the urinary excretion of MHPG in a group of unipolar depressed patients. They measured MHPG excretion before and during the fourth week of treatment with either imipramine hydrochloride or amitriptyline hydrochloride. In the group given imi-

256

S. CALDECOTT-HAZARDET AL

pramine, the mean pretreatment MHPG level was significantly lower in the nine responders than in the seven nonresponders; the converse was found with the group given amitriptyline. Maas et al. (1972) also showed that patients who respond to amphetamine, desmethylimipramine, or imipramine with an elevation of mood have modest increments or no change in urinary MHPG excretion during treatment, whereas patients who do not respond to these drugs have decreased MHPG excretion during treatment (Maas et al., 1972; Fawcett et al., 1972). However, the Beckmann and Goodwin study (1975) showed that although responders t o imipramine appeared to have a smaller decrease in MHPG excretion than that of nonresponders, there was no increase in MHPG excretion during the response to imipramine. Therefore, this study did not confirm the findings of Maas and associates (1972). DeLeon-Jones et al. (1975) presented data indicating that a subgroup of depressed patients who excrete less than normal quantities of urinary MHPG could be identified by the application of the Research Diagnostic criteria (DeLeon-Jones et al., 1975). These criteria are now incorporated into the American Psychiatric Association DSMIII and DSMIIIR. Furthermore, these workers found no significant difference in the execretion of NM, MET, and VMA among any of the diagnostic subgroups or between each patient group and a healthy comparison group. This study suggests that the classification system of primary affective disorder and bipolar depressive disorder may be the most helpful in identifying those patients who excrete low amounts of MHPG. The agitated-retarded and the psychotic-nonpsychotic distinctions were not found to be helpful in identifying depressed subjects who excrete less than normal amounts of MHPG. Of nine studies CSF MHPG in depressed patients, three reported decreased concentrations (Gordon and Oliver, 1971; Post et al., 1973; Subrahmanyam, 19751, one reported increased concentrations (Vestergaard et al., 1978), and in five studies data were normal (Berger et al., 1980; Shaw et al., 1976; Shopsin et al., 1974; Wilk et al., 1972; Oreland et al., 1988). The different results in these studies may be due to differences in diagnostic procedures, sample size, age and sex distribution, as well as biochemical methods. A collaborative study conducted by the National Institute of Mental Health (NIMH) in 1984 (Maas et al., 1984) showed that, consistent with earlier reports, decreases in pretreatment urinary MHPG levels in bipolar depressed subjects serve as a marker for the response to treatment with imipramine. Also, decreased CSF MHPG levels serve the same purpose, again predominantly in bipolar depressed subjects. Moreover, these studies show that decreased CSF 5-HIAA can be a marker for response to amitriptyline in unipolar depressives and that high urinary metanephrine also is a

marker for response t o amitriptyline (Potter et al., 1985).These studies would tend to support the notion of a specificity of action of antidepressants upon neurotransmitter systems. Such a notion has been based on the classical preclinical characterization of tertiary amine tricyclic antidepressants as serotonin uptake inhibitors and of secondary amine tricyclic antidepressants as norepinephrine uptake inhibitors. On the basis of these conventional assumptions, a recent study (Potter et al., 1985) investigated the effects of three antidepressants, with the greatest known specificity of action, on MHPG, HVA, and 5-HIAA levels in the CSF. The expected specificity of action on these neurotransmitters metabolites was not found. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimelidine hydrochloride, a serotonin uptake inhibitor reduced MHPG as well as 5-HIAA concentrations, and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to mostly affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations. This finding is in agreement with animal work showing that long-term administration of antidepressants alter both noradrenergic and serotonergic receptor number andlor function (Charney et al., 1981; Sugrue, 1983). Norepinephrine metabolism in depression As compared with other studies, a report by the NIMH Clinical Research Branch Collaborative Program in Psychiatry (1983) assessed CSF and urinary metabolites in the same person. Measurements were made of MHPG, HVA, and 5-HIAA from each subject’s lumbar CSF and of 24-hr urinary excretion of NE, Epi, and the major metabolites NM, Met, VMA, and MHPG. This study, conducted in 151 hospitalized patients with affective disorders and 80 healthy controls, showed that depressed subjects as a group had higher CSF levels of MHPG as compared with controls. Depressed women also had higher CSF levels of 5-HIAA and depressed men had lower CSF levels of HVA. Urinary MHPG levels were the same in the control and depressed groups. Interestingly, unipolar and bipolar depressed subjects differed in urinary NE and Epi levels. Both transmitters were significantly elevated in the urine of unipolar as compared with bipolar patients and controls (Koslow et al., 1983). Another recent study of the urinary excretion of NE and its metabolites also found that unipolar depressives excreted significantly higher levels of NE and NM when compared with normal controls (Roy et al., 1986~). The data from the two studies just described (Koslow et al., 1983; Roy et al., 1986~)suggested that the metabolism of norepinephrine might be altered in depressed as compared with normal humans. Two hypotheses regarding this change in metabolism have been proposed. Roy et al. (1986a) suggested the

DEPRESSION CLINICAL AND BIOCHEMICAL ASPECTS

possibility that high circulating levels of tyramine release excess NE in depressed patients, thus shifting NE metabolism away from intraneuronal routes. Altered tyramine metabolism was therefore assessed in depressed subjects. However, no significant differences were found between unipolar depressed patients and normal controls for urinary levels of free tyramine. Furthermore, there were no significant correlations between urinary excretion rates of tyramine and those of NE and its metabolites (Roy et al., 1986b). A more recent NIMH collaborative study (Maas et al., 1987) suggested that depressed patients differed from control subjects in their metabolism andor disposition of catecholamines. They found that as a group, depressed patients have a modest but significant increase in the estimated catecholamine synthesis rate compared with healthy control subjects (34.5%for NE and 65% for Epi, even after correcting for the increased synthesis by the patient group). They also found that depressed patients excrete disproportionately smaller amounts of urinary MHPG relative to total catecholamine estimated synthesis than do healthy control subjects. In contrast to NE, Epi, and MHPG, the increased amounts of NM, Met, and VMA excreted by depressed patients, vis-a-vis controls, are proportional to each other as well as to the increased catecholamine synthesis seen with depressed patients. The differences in the patterns of catecholamine and metabolite excretion are due principally to the unipolar patients, with the bipolar patients being generally similar to the control subjects. Given these findings, these investigators suggest that the depressed patients excrete more Epi and NE than do normal subjects, not because of increased synthesis alone but because of an increased release of catecholamines from adrenergic tissues (Maas et al., 1987). The most recent published report of the NIMH group (Davis et al., 1988) further supports the above findings. One hundred and thirty two drug-free, severely depressed patients and 80 healthy controls were studied. Forty-five percent of depressed patients excreted markedly elevated levels of urinary epinephrine and metanephrine, while only 5% of healthy controls did so. Using gaussian mixture distributions, they identified two subgroups of depressed patients: one excreting normal levels and the other excreting high levels of urinary Epi, Met, NE, and NM. CSF homovanillic acid levels were also low in a subgroup of depressed patients. When analysed by subgroup, the elevated Epi and Met group had markedly lower cerebrospinal fluid homovanillic acid levels than controls, whereas depressed patients with normal urinary catecholamine levels did not (Davis et al., 1988). The studies reviewed above show complex relationships between norepinephrine and its metabolites measured in CSF or urine relative to diagnostic subgrouping. A factor that could account for such diversity is the relative severity of disease (i.e., there is wide variability

25 7

in the clinical behavior of individuals affected with depression or mania). Another factor that affects differences in the rate of excretion of these metabolites could be diurnal variation. The level of plasma free MHPG in depressed patients compared with controls is inconsistent across studies (Kopin et al., 1984; Roy et al., 1986d; Siever and Uhde, 1984). One possible explanation for these inconsistencies is that central and peripheral noradrenergic activity varies across the day (Carlsson et al., 1980; Linsell et al., 1985). Norepinephrine and MHPG concentrations exhibit a circadian variation in human brains examined postmortem (Carlsson et al., 1980). Also, daily fluctuations have been observed in plasma levels of norepinephrine and total plasma MHPG (Linsell et al., 1985; Demet et al., 19821, as well as in the urinary excretion of MHPG (Giedke et al., 1982; Wehr et al., 1980). The unconjugated or free concentration of MHPG in plasma is highly correlated with CSF MHPG levels in human subjects (Jimerson et al., 1981). The timing of the variation of urinary and plasma MHPG has been reported to be shifted to an abnormally early position in depressed patients compared with normal controls (Demet et al., 1982; Wehr et al., 1980). These differences in phase could account for differences in plasma free MHPG levels between patients and controls observed in cross-sectional, singletimepoint studies. Increased variability in the timing of these variations, as has been reported for other circadian rhythms in depressed patients (Pflug et al., 1981; Goldstein et al., 1980),would tend to obscure differences in plasma MHPG levels when measured at a particular time of day. Also diurnal variations in plasma MHPG can be evoked by changes in physical activity, posture, or other factors controlled by constant routine (Sack et al., 1988). Variations in these physical variables in depressed patients could therefore further obscure differences in MHPG levels. It is clear that, in the aggregate, these recent findings on the metabolism and disposition of catecholamines have changed the view of the etiopathogenesis of depressive disorders. Further investigations are required in humans and laboratory rodents with regard to the hypothesis of neurotransmitter availability. Alternatively these findings could support a role for pre- and postsynaptic receptors in depression. Antidepressant effects on receptors (Table 111) F'resynaptic A-2 receptors Alpha-2 adrenergic receptors are thought to be located on the cell body and presynaptic membranes of central noradrenergic neurons (Cedarbaum and Aghajanian 1971; Langer et al., 1980) as well as on postsynaptic norepinephrine sensitive neurons (Byland and UPrichard, 1983). When activated by catecholamines, the presynaptic receptors inhibit nerve impulses and reduce the release of norepinephrine. Since these receptors inhibit norepinephrine release, Alpha-2 receptor subsensitivity would be expected to increase norepi-

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nephrine release. This effect was illustrated using tritium-labeled tricyclic antidepressants that bind with high affinity to the Alpha-2 adrenergic receptors (McMillen et al., 1980). Several tricyclic antidepressants, when given chronically, reduced the sensitivity of brain Alpha-2 receptors (Svenson and Usdin, 1978). Reduced density of these receptors was also noted in several brain regions of the rat after chronic, but not acute, administration of amitriptyline (Smith et al., 1981).The therapeutic lag observed during treatment of depressed subjects with antidepressants (i.e., approximately 21 days before significant therapeutic effects are evident) would be in keeping with the Alpha receptors becoming subsensitive and thus leading to increases in norepinephrine release. A variety of studies have, in fact, indicated that changes in presynaptic Alpha-2 receptors may be, in part, responsible for the therapeutic effects of various antidepressant drugs (U'Prichard et al., 1978; Crewes and Smith, 1978; Garcia-Sevilla et al., 1981; Menkes et al., 1980; Siever et al., 1981). Studies also suggest that Alpha-2 adrenoceptors may have a role in the pathogenesis of depression and mania. Clonidine, and Alpha-2 receptor agonist, has been reported to have antimanic effects (Freedman et al., 1980; Jimerson et al., 1980; Jouvent et al., 1980; Giannini et al., 1983; Zubenko et al., 1984; Adler et al., 1982). Such data are in keeping with a reduced release of NE into the synaptic cleft by clonidine's enhancement of Alpha-2 receptor function (Cedarbaum and Aghajanian, 1977; Aghajanian, 1984; Price et al., 1984). Predictably the antagonism of Alpha-2 receptors by yohimbine produced relief from depression, albeit short-lived, in a very small number of subjects (Price et al., 1984; Starke et al., 1975). Increased levels of MHPG in rat brain after chronic administration of tricyclic or nontricyclic antidepressants (McMillen et al., 1980; Przgalinski et al., 1981) further support a change in norepinephrine systems with antidepressants. However, the increase in norepinephrine in rat brain occurs immediately after an injection of desmethylimipramine (Huang, 1979a,b), and Alpha receptor changes in response to antidepressants are not immediate. Also, several antidepressants fail to produce subsensitivity of Alpha-2 receptors in the brain, and mianserin even produces supersensitivity in Alpha2 receptors (Cerrito and Raiteri, 1981; Sugrue, 1980). A recent study using hypothalamic rat preparations treated with clonidine suggests that the functional subsensitivity seen in synaptosomes after desmethylimipramine administration may not be related to Alpha-2 adrenoreceptor regulation (McWilliams and Campbell, 1987). The data therefore indicate that, while presynaptic Alpha-2 adrenergic receptors modulate norepinephrine release, their distinct role in the etiopathogenesis of depression is not clear. Several recent studies in humans have shown an increase in platelet Alpha-:! adren-

ergic receptor number in depressed patients with no change in the apparent affinity of the receptor for its ligand (Garcia-Sevilla et al., 1981; Kafka et al., 1980; Mitrius et al., 1983; Healy et al., 1983; Siever et al., 1984b). Others did not show any such differences (Pimnoul et al., 1983; Daiguji et al., 1981; Stahl et al., 1983; Lenox et al., 1983). These discrepencies may be due to differences in the ligands used for assaying receptor changes. Long-term lithium treatment was also reported to be associated with a decrease in the number of high-affinity Alpha-2 adrenergic receptors and with an increase in the platelet aggregation response induced by epinephrine (Garcia-Sevilla et al., 1986). However, the number of patients in the study was too small t o permit definitive conclusions. Finally, recent data indicate that only a small portion of Alpha-2 adrenergic receptors in the CNS appear to be located presynaptically, as measured by available radioligand techniques (U'Prichard et al., 1979; Morris et al., 1981).However, selective Alpha-2 receptor agonists and antagonists still may physiologically and behaviorally reduce or enhance catecholamine activity (Anden et al., 1976; Braestrup, 1974; Cedarbaum and Aghajanian, 1976; Starke and Altman, 1973; Drew et al., 1977). Behavioral responses to pharmacologic or environmental challenge could result from subsensitive presynaptic receptors or supersensitive postsynaptic receptors (Schwartz et al., 1978). It is also important to make a distinction between changes in receptor numbers and changes in receptor sensitivities; these two concepts are not interchangeable. In addition, one must be mindful of relationships between different types of receptors when assessing the response from a challenge to a particular receptor type. For example, opposite responses of Alpha-:! and Beta receptors were observed in cortical slices when incubated, in vitro, with isoproterenol (Maggi et al., 1980a,b). Opposite responses also occurred in the cortex after in vivo, intraventricular infusions of isoproterenol (Wang and U'Prichard, 1980). On the other hand, antidepressants can induce decreases in both Alpha-:! and Beta receptor densities (Smith et al., 1981; Cohen et al., 1982). However, the temporal pattern of change in Alpha-2 receptors appears to be more rapid than for Beta receptors (Smith et al., 1981; Cohen et al., 1982). Animal models, based on challenges known to produce affective disorders in man, also show changes in Alpha receptors, particularly Alpha-2 receptors. Reserpine treatment increases both Alpha-1 and Alpha-2 adrenergic receptor densities in the CNS (U'Prichard and Snyder, 1978). Furthermore, Yohimbine, a specific Alpha-:! receptor antagonist, blocks increases in Beta receptor number in the cortex induced by clonidine (an Alpha-2 agonist) (Johnson et al., 1980).Yohimbine also blocks clonidine-induced enhancement of isoproterenolstimulated cyclic AMP in the brain stem (Johnson et al., 1980).

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Following unilateral olfactory bulbectomy in rats, a trols despite similar MHPG responses. The authors condition ensues that is thought to be similar to human concluded that the abnormally increased cortisol redepressive disorders. In addition to changes in other sponse to yohimbine suggests a relative subsensitivity receptor systems, Alpha-2 receptors are decreased by of postsynaptic Alpha-2 adrenergic receptors in depres50% in the contralateral bulb (Cairncross et al., 1979). sion (Price et al., 1986). Experiments in the Roman high and low avoidance Alpha-1 receptors. Alpha-1 receptors are generally strain of rats also show an increase in Alpha-2 receptors accepted as being located a t postsynaptic membranes. in the CNS of animals that display behavior resembling Norepinephrine released into the synaptic space actidepression (Cohen and Campbell, 1984). The studies vates Alpha receptors of the postsynaptic neurons. Exreviewed indicate the need for further exploration of the amination of the effects of chronic administration of the role of Alpha-:! adrenergic receptors in depression. tricyclic antidepressants in rodents reveals increased numbers of Alpha-1 receptors or increased affinity for Alpha-1 agonists (Charney et al., 1981; Dillier et al., Postsynaptic receptors 1978; Hoffer et al., 1971; Huang et al., 1980; Menkes et al., 1983a,b; Vetulani et al., 1984; Plaznik et al., 1984). Until recently, the most generally accepted theory of Long-term administration of tricyclic antidepressants antidepressant action has been that these drugs en- also produces increased sensitivity of postsynaptic cells hance neurotransmission through relative increases of to signals mediated by Alpha-1 receptors (Huang et al., monoamine levels a t synaptic junctions in the brain. 1980; Menkes et al., 1980; Meyerson et al., 1982). It has Typical antidepressants, such as the tricyclics, have been noted that many tricyclic antidepressants weakly been hypothesized to cause this increase by inhibiting inhibit Alpha-1 receptors (Richelson and Nelson, 1984). the neuronal reuptake process, which results in the This has led to the suggestion that weak blockade may prolongation of neurotransmitter effects at the postsyn- be sufficient to prevent down-regulation of Alpha-1 and aptic receptor site. MA0 inhibitors (MAOIs) have been consequent desensitization (Starke et al., 19751,in conreported to increase the intraneuronal stores of neuro- trast to Alpha-2 and Beta receptors. transmiters, thereby making more monoamine availNeuroleptics that have considerable Alpha-1 antagoable for release into the synaptic cleft. However, irrefut- nistic properties (Richelson and Nelson, 1984; Peroutka able evidence that these are the main mechanisms et al., 1977) are useful in the treatment of mania. It has involved in antidepressant action is lacking; in fact, therefore been suggested (Starke et al., 1975) that several observations suggest that other mechanisms Alpha-1 receptors may play an important role in the may be important. First, three decades of clinical expe- pathogenesis of mania. Finally, it is noteworthy that rience with antidepressant therapy have shown that lithium, at doses sufficient to control mania, inhibits therapeutic doses usually take 7-21 days for a clinical dephosphorylation of inositol-l-phosphate (Sherman response to occur; on the other hand, uptake and MA0 et al., 1981). Thus, the second messenger polyphosphoinhibition, respectively, are produced immediately after inositide system cannot couple to Alpha-1 receptors. single doses of the active compounds. Second, some Preliminary data suggest that chronic lithium adminisdrugs, which are neither blockers of monoamine re- tration increases Alpha-1 receptor density (Rosenblatt uptake nor MA0 inhibitors, are clinically effective anti- et al., 1979). depressants. Finally, noradrenergic subsensitivity folBeta receptors. Although two subtypes of Beta receplowing antidepressant drug administration is reported tors (B1 and B2) are known t o exist, most research using t o be linked t o a decrease in the number of Beta- antidepressant drugs has not distinguished between adrenergic receptor sites (Banarge, 1977). These obser- them. However, it is important to note that the B1 vations have contributed to a shift in the focus on subtype is thought to be primarily associated with antidepressant mechanisms from transmitter to recep- neuronal function. The bulk of the B2 receptors are tor changes that occur following prolonged drug admin- probably localized in glial cells and possibly on cerebral blood vessels (Janowsky and Sulser, 1987). istration. Alpha-2 receptors. Depression-related receptor changes A variety of antidepressant treatments, including can occur both pre- and postsynaptically, and we al- tricyclic antidepressants, monoamine oxidase inhibiready discussed presynaptic changes in Alpha-2 recep- tors, atypical antidepressants, and electroconvulsive tors. Evidence for postsynaptic changes in Alpha-2 re- treatment, all cause a subsensitivity of Beta-adrenergic ceptors comes from a study by Price et al. (1986). These receptors in rat brain (Sulser et al., 1978). The time investigators administered yohimbine (an Alpha-2 course of Beta-receptor subsensitivity produced by antiadrenergic antagonist which increases norepinephrine depressants is dose dependent. However, it is relevant turnover) to subjects with major depression and healthy to the mechanism of antidepressant action that, a t controls. Plasma cortisol levels were used to assess HPA therapeutically relevant doses, subsensitivity of the axis activity. The cortisol response to yohimbine was @receptors is obtained between 7 to 21 days. This significantly greater in depressed patients than in con- parallels the lag seen in the onset of therapeutic re-

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sponses in depressed subjects (Oswald et al., 1972; Klein et al., 1980). A detailed review of antidepressant treatments that have been shown to produce subsensitivity of betaadrenergic receptors in brain has recently been published (Sulser, 1983). The review includes classical tricyclic antidepressants (both tertiary amines, which predominantly block the uptake of 5-HT, and secondary amines, which are more selective in blocking the uptake of NE), MA0 inhibitors, atypical antidepressants such as iprindole (which does not inhibit the uptake of either NE or 5-HT) and mianserin (a tetracyclic that blocks 5-HT receptors and decreases serotonergic activity), as well as the more selective 5-HT uptake blocker zimelidine. All these compounds decrease the sensitivity of Beta-adrenergic receptors. It is noteworthy that ECT, which is considered to have a faster onset of action than these drugs in man, has also been shown to produce rapid down-regulation of the NE receptor system (Gillespie et al., 1979). Finally, lithium has been shown to have antidepressant properties in some patients (Sulser et al., 1978). It has also been reported to decrease the sensitivity of Beta-adrenergic receptors (Ebstein et al., 1980). Brain postmortem suicide studies have also measured Beta adrenergic receptors. One study reported no alterations in Beta-adrenergic receptor binding using dihydroalprenolol (DHA) (Meyerson et al., 1982). Another study reported an increased number of binding sites (Bmax) with no change in binding site affinities (Kd) in six suicide victims and matched controls (Zanko and Biegon, 1983). A more recent study showed a 73% increase in beta adrenergic receptor binding in frontal cortex of suicide victims using DHA compared to controls (Mann and Stanley 1986). Many variables need to be taken into account in the interpretation of postmortem data and suicide studies. For example, while approximately 50% of suicide victims are diagnosed as depressed, this is generally a heterogenous diagnostic grouping. The postmortem interval (i.e., the period between death and the time at which the brain tissue is removed and frozen) is also important. The type of death (e.g.,overdoses, bodily wounds, traumas, carbon monoxide) may influence biochemical parameters. Another important variable is age; a significant increase in cortisol DHA binding with age was seen in the Mann and Stanley study (1986) described above. Finally, the finding of increased P-receptor binding, shown by the studies above, is in the opposite direction from receptor changes reported following the antimortem use of antidepressants (that down-regulation of beta receptors may be linked with the therapeutic effect of antidepressants). Antidepressant effects on secondary messengers Secondary messenger systems, such as the norepinephrine-receptor-coupled adenylate cyclase system,

produce a series of events within the postsynaptic neuron (e.g., protein changes and ion channel changes) in response to the occupation of a receptor by a neurotransmitter or hormone. Functioning of these secondary messenger systems, like the postsynaptic receptors they connect to, has been reported to be altered in depression. Before describing the depression data, a brief explanation of the functioning of the adenylate cyclase system will be provided. Substances that are a part of, or that affect, the adenylate cyclase system include hormones and certain neurotransmitters (e.g., norepinephrine), guanine nucleotides and their binding proteins, other adenylate cyclase modulators, and changes in the properties of neuronal membranes and cytoskeletons. Hormone and transmitter effects on adenylate cyclase activity involve the interaction of at least three components: the hormone or neurotransmitter receptor (R),a guanine nucleotide-binding protein complex (N), and a catalytic moiety of adenylate cyclase (C). Guanosine 5’-triphosphate (GTP)-binding proteins serve two major functions: (1) they regulate the binding of hormones to their receptors, and (2) they “couple” or transduce the signal of hormone binding into either an increase or decrease in cyclic adenosine monophosphate (CAMP). Specifically, an occupied receptor interacts with a stimulatory (Ns) or inhibitory (Ni) guanine nucleotide-binding protein. When GTP binds to this N protein, the protein alters the catalytic moiety of adenylate cyclase, and CAMPlevels are increased or decreased. Termination of the modulation of catalytic activity may be accomplished by hydrolysis of GTP to guanosine 5‘-diphosphate (GDP), by a GTPase enzyme that is associated with the protein complex (Orly and Schramm, 1975). Studies with bacterial toxins have provided physical evidence for the existence of Ns and Ni proteins (Northrup et al., 1982; Katada and Ui, 1982). In addition, photoaffinity probes, which covalently label GTP-binding proteins, suggest that separate substrates may mediate hormonal inhibition or stimulation of adenylate cyclase (Rasenick et al., 1984). Other substances that modulate adenylate cyclase activity include two non-GTP-binding peptides of 35 and 9 kDa, which are thought to act through the Ns and Ni proteins (Kent et al., 1980). Also, cytoskeletal elements of neurons and calmodulin may regulate adenylate cyclase (Rasenick et al., 1981; Brostrom et al., 1979) via interactions with N proteins andlor directly with the catalytic moiety of adenylate cyclase. Membrane lipids have been reported to be necessary for the hormonemediated activation of adenylate cyclase (Wolfe et al., 19681, and changes in membrane fluidity can affect the activation of adenylate cyclase (Orly and Schramm, 1975,1977; Rasenick et al., 1981). Regarding depression and secondary messengers, reserpine and propranolol, drugs known to precipitate depressive reactions in man, increase the sensitivity of the norepinephrine, receptor-coupled adenylate cyclase

DEPRESSION: CLINICAL AND BIOCHEMICAL ASPECTS

system in the brain (Dismukes and Daily, 1974; Kalisker et al., 1974; Palmer et al., 1973; Vetulani et al., 1976a; Wolfe et al., 1978). On the other hand, many types of clinically effective antidepressants decrease the sensitivity of this system (Wolfe et al., 1978; Vetulani and Sulser, 1975; Vetulani et al., 1976b; Frazer et al., 1978).However, some atypical antidepressants produce either no effect or inconsistent down-regulation, in the NE receptor-coupled adenylate cyclase system (Sulser, 1983). These antidepressants include fluoxetine, trazodone, and buproprion. The majority of experimental data suggest that up- or down-regulation of the NE receptor-coupled adenylate cyclase system is agonist-specific and inversely proportional to the availability of NE at noradrenergic beta receptors. However, changes in adenylate cyclase, by atypical antidepressants that do not block reuptake of NE (iprindole, mianserin, and zimelidine), suggest that other regulatory mechanisms may also exist. Some antidepressants may have a direct effect upon second messenger systems, as data with trazodone seem t o indicate (Maj et al., 1979~). For example, reports have indicated that the coupling of N proteins with the adenylate cyclase catalytic moiety may be regulated directly by antidepressant treatment (Menkes et al., 1983; Andersen et al., 1984), although conflicting results exist (Duman et al., 1985). Conclusions In closing, this review of the role of adrenergic systems, in the etiopathogenesis of affective disorders, points to significant progress in research on this topic. However, the data also highlight the need for clarification of pre- and postsynaptic mechanisms underlying the causes of depressive disorders and the action of antidepressants.

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pathogenesis and/or therapeutic correction of the neuronal dysfunction leading to affective disorder. The sheer volume of information concerning serotonin and depression is overwhelming for any single review to cover in all its detail. During the past decade, there have been a number of reviews specifically on this topic. Perhaps the most extensive of these is the review by Meltzer and Lowy (1987). At least a half-dozen additional reviews of this topic have appeared since Meltzer and Lowy (1987)but, with respect to the presentation of primary data, 1987 will be taken as the starting point for most of this review. For much of the information published prior to 1987, the reader will be referred to earlier reviews. Three general classes of information relating to the serotonin hypothesis of depression are discussed in this review. These include the pharmacologic action of drugs used t o treat depression, studies of biochemical measures in humans with affective disorders, and the longterm effects of antidepressant therapies (ADTs) on the neurochemistry of laboratory animals, performed almost exclusively in rodents. One reason the serotonin hypothesis of depression remains a hypothesis is that the major lines of evidence cannot critically test the hypothesis. Studies of long-term ADT effects in rodents are subject to all the caveats of comparative studies, and the very real possibility that ADTs have different effects in depressed patients than in normals. For example, how does one tell when a rat is clinically depressed? While many of these difficulties are not insurmountable, most of the published data as of this writing are subject to these criticisms. The last section of this chapter will address means of circumventing these criticisms with recent technical advances.

Pharmacology of the serotonin system Serotonin is synthesized within neurons by two enzymatic steps. The amino acid tryptophan is first conSEROTONIN (D.G. Morgan) verted to 5-hydroxytryptophan (5-HTP) by the enzyme The concept that depression in humans may result tryptophan hydroxylase, a specific marker for serotonfrom deficient activity in the serotonergic system was ergic neurons and terminals, and is subsequently decarfirst elaborated during the late 1960s (Coppen, 1967). boxylated to serotonin (a.k.a. 5-hydroxytryptamine) by Over the past quarter-century, this hypothesis has been aromatic acid decarboxylase (the same enzyme as subject to multiple tests of its veracity. It has withstood DOPA-decarboxylase in dopaminergic neurons). The most challenges, yet cannot by any means be accepted tryptophan hydroxylase step is rate limiting, and the as proven. Much of the difficulty in confirming or deny- enzyme is typically not saturated with its substrate ing this hypothesis is seated in the overwhelming com- tryptophan. Released serotonin is inactivated primarily plexities of the group of disorders referred to as depres- through reuptake via the serotonin transporter, a sodision, and the technical difficulties in directly testing the um-dependent transmembrane carrier. Within neurons predictions of the hypothesis. The data in support of the or glial cells, the serotonin is metabolized via monoamhypothesis, reviewed here, must be considered circum- ine oxidase and aldehyde reductase to B-hydroxyinstantial. It is important to consider that many other doleacetic acid (5-HIAA).This metabolism within nerve neurotransmitter systems have also been proposed to terminals does not require the initial release of the play a role in depression and, most likely, the truth serotonin, limiting the usefulness of 5-HIAAas an index involves some combination of these proposals, and in- of serotonin release. There are autoreceptors on the teractions between the transmitter systems of the serotonergic neurons that regulate activity in the serobrain. Nonetheless, there is overwhelming support that tonin system in a negative feedback fashion by inhibitthe serotonergic system is at least involved in the ing the activity of serotonergic neurons in the somatic

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regions and inhibiting release of serotonin in the terminal regions. Postsynaptically, there are an increasing number of serotonin receptors. The S-1 (also known as 5HT-1) receptors, traditionally labeled by [3Hlserotonin have at least four subtypes, designated S-la, S-lb, S-lc, and S-ld. The S-2 (5HT-2) receptor class is labeled most commonly with [3Hlketanserin, and thus far has resisted attempts to find subtypes, although many assay conditions for the detection of these binding sites are heterogeneous (Morgan et al., 1984). Traditionally, the S-1 (5HT-1) class of receptors is believed to stimulate adenylate cyclase, while the S-2 (5HT-2) class, in a t least some locations, activates inositol phosphate metabolism. Antidepressant actions on the serotonergic system Monoamine oxidase inhibitors (MAOIs). Monoamine oxidase A is the isozyme used to metabolize serotonin and norepinephrine (Murphy et al., 1987). Presumably, by impeding the metabolism of serotonin, these drugs will increase the serotonergic synaptic activity, and certainly these drugs do increase serotonin levels within the brain. However, it is uncertain what the acute effects of these drugs are on synaptic cleft levels of serotonin, since the metabolism is intracellular. Studies using microdialysis to measure extracellular serotonin concentrations following MAOIs will undoubtedly resolve this issue in the near future. Typical drugs of this class are phenelzine and tranylcypromine. Tricyclic antidepressants (TCAs). Most agents of this class share the property of inhibition of serotonin uptake, norepinephrine uptake, or both, and are typically inactive in blocking dopamine uptake (Bryant and Brown, 1986). Importantly, many of these compounds also have the capacity to antagonize postsynaptic serotonin receptors at concentrations similar t o those required for uptake inhibition (Wander et al., 1986).These drugs will augment serotonergic transmission by prolonging the residence time of serotonin in the synapse following uptake blockade. Typical drugs of this class include imipramine, amitriptyline, doxepin, and desipramine. Serotonin precursors, 5-HTP and tryptophan. Based on the serotonin deficiency hypothesis of depression, these compounds have been tested for clinical effectiveness in depression as replacement therapies. Tryptophan has been largely ineffective by itself as an ADT but has been reported to potentiate the effectiveness of MAOIs in accelerating recovery from depression (see Meltzer and Lowy, 1987; Grahame-Smith, 1989; Cowen, 1990).Because tryptophan concentrations are subsaturating for tryptophan hydroxylase activity, tryptophan loading elevates serotonin levels in brain, which may have some facilitation of serotonergic transmission. However, tryptophan loading also influences the synthesis of other monoamine transmitters, and a stimula-

tion of serotonergic activity has yet to be demonstrated (Van Praag, 1986). The immediate serotonin precursor, 5-HTP, is rapidly converted to serotonin in the CNS, but it too has influences on other brain monamine systems (Van Praag, 1983).5-HTP does have some ADT efficacy when administered alone but, when combined with TCAs, appears more effective in reducing the symptoms of depression than either drug alone (Van Praag, 1986). Van Praag et al. (1987) believe that those patients with low CSF 5-HIAA (see below) are most responsive to the serotonin precursor therapies, and that the major effect of serotonin potentiating drugs is to reduce the anxiety/ aggressive components of depression. Serotonin uptake blockers (SUBS). The general absence of pharmacological selectivity of the TCAs prompted several groups to develop drugs which were selective inhibitors of serotonin uptake, in part to evaluate whether it was the activity a t the serotonin or norepinephrine transporters that was primarily responsible for their efficacy of ADTs. This new generation of drugs has been tested extensively and found to possess ADT potency equivalent to the more traditional TCAs and drugs that have a selective action on norepinephrine uptake (Lemberger et al., 1985; Nystrom et al., 1986; Skrumsager and Jeppesen, 1986; Schatzberg et al., 1987; Burrows et al., 1988; Montgomery et al., 1988). Nystrom and Hallstrom (1987) found that depressed patients unresponsive to either a SUB or specific noradrenergic uptake blocker, were typically responsive when the other drug was substituted for the first, suggesting two subtypes of depression, one due to serotonergic deficiency and the other to noradrenergic deficiency. However, using equally selective drugs, Emrich et al. (1987) found that only 20% of patients not responding to one of the drugs responded to the other, suggesting that there are not distinct “serotonergic”and “noradrenergic”depressions. Additional studies will be required to resolve this important issue, and to identify patients which might selectively respond to serotonergic or noradrenergic drugs. While SUBs potentiate serotonergic transmission by an action similar to that described for the TCAs above, the spectrum of side effects for the SUBs is different than the TCAs. Drugs in this class include fluoxetine, fluvoxamine, citalopram, and zimelidine, although the latter drug is no longer in use because of toxicity. Serotonin receptor agonists. Perhaps the most recent addition to the armamentarium for ADT is a class of drugs acting as agonists a t the S-la receptors. While originally used for treatment of anxiety, these direct agonists are now recognized as effective against depression as well (Schweizer et al., 1986; Amsterdam et al., 1987; Robinson et al., 1989). These drugs directly activate postsynaptic S-la receptors, and presynaptic S-la autoreceptors on serotonergic cell bodies and terminals, mimicking the actions of serotonin. Drugs of this class include buspirone, gepirone, and ipsaperone.

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Other therapeutic manipulations. In addition to the above ADTs, two other therapeutic manipulations deserve mention. The first is the effect ofp-chlorophenylalanine (pCPA), an inhibitor of tryptophan hydroxylase, on antidepressant action. Shopsin and Feiner (1984) summarize their studies demonstrating that pCPA administration to patients responding to either TCAs or MAOIs induced a rapid relapse to the depressed state, which was reversible with removal of pCPA and continuation of the ADT. This would imply that facilitation of serotonergic function was one therapeutic action of these ADTs and that inhibition of serotonin synthesis reinstated the symptoms of depression. Importantly, these investigators, found that Alpha-methyl-p-tyrosine, an analogous inhibitor of dopamine and norepinephrine synthesis, failed to produce a relapse in patients responding to traditional ADT, implying that facilitation of norepinephrine synthesis was less important in therapeutic efficacy of these treatments. An analogous approach was described by Price et al. (19901, in which patients receiving ADT were administered a diet deficient in tryptophan. This diet reduced plasma tryptophan by 90% and induced a depressive relapse in two-thirds of the patients, attributed to inhibition of serotonin synthesis. Electroconvulsive shock therapy (ECT). Electroconvulsive shock therapy appears to be the most effectiveof the ADTs for severe depression (Meltzer and Lowy, 1987; Lerer, 1987).The seizures produced by such treatments must be accepted as influencing virtually every transmitter system in the brain, including serotonin. The long-term influences of repeated ECT on serotonergic function are discussed in the section on antidepressant effects on the neurochemistry of animals. Lithium. While also used to control mania, lithium is effective in the treatment of depression, especially when combined with TCAs, or when used prophylactically (Bunney and Garland-Bunney, 1987). Evidence converging from clinical and preclinical sources now suggests that one action of lithium is enhanced serotonergic activity (Bunney and Garland-Bunney, 1987; Goodnick, 1987), although the mechanisms by which this facilitation is achieved are not certain. To summarize, a number of different ADTs are effective in accelerating the recovery of depressed patients. Each ADT has its own spectrum of actions on central nervous system function. However, one common action of virtually all ADTs is an effect on the serotonin neurotransmitter system, usually one of facilitation. However, it is critical to realize that no ADT is effective immediately; most require 1-3 weeks of administration to significantly improve the symptoms of depression. Hence, it is the long term changes in brain structure and function brought about by the acute effects of these ADTs that underlie the therapeutic benefit. Data concerning the long-term influences of these ADTs are dis-

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cussed in the section on antidepressant effects on the neurochemistry of animals. Biochemical measures in humans (Table 11) Cerebrospinal fluid (CSF) 5-HIAA One window on CNS function in humans is the CSF level of neurotransmitter metabolites, the major serotonergic metabolite being 5-HIAA. Over the past two decades, a number of studies have examined 5-HIAA content in lumbar punctures from depressed patients and matched controls. While initial studies reported consistent reductions in CSF 5-HIAA in subsets of depressed patients, many studies have failed to replicate these findings (discussed in Meltzer and Lowy, 1987; Coppen and Doogan, 1988; Grahame-Smith, 1989). Much of the difficulty in replication may reflect confounds in the actual measurement of CSF 5-HIAA.A number of unrelated variables such as height, age, gender, body weight, diet, time of day, and season influence the resultant CSF 5-HIAA values (Asberg et al., 1984). In addition, lumbar CSF 5-HIAA may reflect mainly the spinal metabolism of serotonin, which may not covary with brain 5-HIAA. Traskman-Bendz et al. (1986) summarize the data that implicates low CSF 5-HIAA in psychiatric patients with suicidal behavior irrespective of the clinical diagnosis. Such patients are characterized as aggressive, hostile, anxious and impulsive. Van Praag (1986) believes that more reliable CSF 5-HIAA measures are obtained when export of 5-HIAA out of the CSF is blocked by administration of the acid transporter inhibitor probenecid. Using this measure, Van Praag (1986)reports that low CSF 5-HIAA is associated with more violent suicide attempts, and is correlated with depression in other disorders, like Parkinson’s disease. Murderers who act in a premeditated fashion tend to have normal 5-HIAA, while those who act impulsively tend to have low CSF 5-HIAA (Van Praag, 1986). In general, individuals exhibiting antisocial behavior of many types have low CSF 5-HIAA (Brown and Linnoila, 1990). Other studies have reported conflicting results. Treatment of depressed patients with TCAs, SUBS, or MAOls, instead of increasing CSF 5-HIAA back to normal, further reduces the CSF 5-HIAA (Cowen, 1990). A recent study examined CSF serotonin in depressed patients and found a two fold elevation in depressed cases which was greatest in the endogenous subtype (Gjerris et al., 1987). No change in 5-HIAA was found in the depressed patients, nor were any correlations found with respect to suicidal thoughts, however, the CSF 5-HIAA content did decline after ADT. In a large study of 132 patients and 80 controls, Davis et al. (1988) found no difference in 5-HIAA between controls and depressed patients. Surprisingly, the control distribution was bimodal, while the distribution for depressed patients was unimodal with a mean in between

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latter data may be questioned, because the K, value reported in this study was 0.7-1 M serotonin, while most other studies report K, values in the micromolar range. It should also be mentioned that both diurnal and seasonal variations in platelet serotonin uptake have been reported (diurnal: Healy et al., 1986b;Modai et al., Platelet serotonin uptake 1986; Jerushalmy et al., 1988; seasonal: Egrise et al., As mentioned previously, serotonin released at cen- 1986; Malmgren, 19891,and these oscillations appear to tral synapses is inactivated by removal from the syn- be distorted in depressive patients, possibly producing apse via a serotonin transporter, or uptake system. This times of day or year when differences in serotonin transmembrane protein carrier binds serotonin in the uptake between depressives and controls may be diffiextracellular space, and transports it into the cell and cult to detect. Future studies will need to control for concentrates it, using cotransported sodium as an en- these variables. In summary, there does appear to be a significant ergy source. As with all enzymes, it has properties of V, (maximal rate of activity under ideal conditions), reduction in platelet serotonin uptake in major, endogand K, (the concentration of the substrate serotonin enous, nondelusional depression, but not in other psyactivity). The V, indi- chiatric disorders. This reduction is normalized in paproducing one-half of the V, cates the number of transporter molecules, while the K, tients responding to ADTs of most types and serves as a reflects the affinity of the transporter molecule for its state marker for major depression. Unfortunately, the substrate. Blood platelets, like serotonergic neurons, variation within normal control patients is sufficiently also store and release serotonin, and they too have a great that platelet serotonin uptake is unlikely to serve serotonin transporter that is very similar, if not identi- as a diagnostic marker for major depression nor is it cal, to the transporter found in the brain. Because of the predictive of a response to specific ADTs. greater accessibility of blood, considerable research has L3H]Imipramine binding to platelets been performed on this platelet serotonin transporter. Antidepressant drug-binding sites on platelets and In a review of over a dozen papers describing changes within the CNS have been known for more than a in platelet serotonin uptake in depressed patients, decade to modulate the uptake of serotonin in both of Healy and Leonard (1987) argue forcefully that a decline in the V, but not the Q,of serotonin uptake is a these structures. One means of measuring these bindconsistent finding in major depression. Moreover, this ing sites is to use radioligands that have high affinity for is normalized in patients responding them, such as [3H]imipramine. However, most studies reduction in V, to ADTs. Unlike the V, the K, increases in both with r3HIimipramine have defined nonspecific binding responders and nonresponders when they are treated of the radiolabeled compound with structurally similar with drugs that have measurable serotonin uptake nonradioactive compounds, such as desipramine or inhibition. These uptake inhibitors compete with sero- chlomipramine. This choice of displacing drugs is unfortonin for the binding site on the transporter, reducing tunate, because it is now apparent that they displace the apparent affinity of the transporter for serotonin. [3Hlimipramine not only from a high-affinity site assoRausch et al. (1986)claim that the decrease in serotonin ciated with the serotonin transporter, but also a loweruptake is specific for unipolar depression and is not affinity site that is nonproteinaceous, and not regionfound in bipolar affective disorder, other affective disor- ally localized with serotonin uptake in the brain (Reith ders, or nonaffective psychoses. Healy et al. (1986a) et al., 1983; Hrdina et al., 1984; Marcusson et al., 1985). found that deluded depressives had normal serotonin Thus, the results from many of these studies may be uptake, while nondeluded depressives had reduced up- questioned because of this technical artifact. take that normalized after a therapeutic response. More recent analyses have used serotonin or more speModai et al. (1989) examined serotonin uptake in ado- cific serotonin uptake inhibitors that are not tricyclics lescent psychiatric inpatients and found no significant (paroxetine, citalopram) t o displace [3H]imipramine reductions in platelet serotonin uptake, although those binding in a biphasic manner, with only the highclassified with affective disorder plus schizoaffective affinity components of the displaceable binding corredisorder tended to be lower. Faludi et al. (1988) found sponding to the authentic serotonin transporter (Sette the expected decrease in serotonin uptake in depres- et al., 1983; Marcusson et al., 1986; Mellerup and sives, but there was no correlation with the degree of Plenge, 1986). In part, because of the heterogeneity of depression. The only negative finding since the Healy the imipramine binding site, it was proposed that imiand Leonard (1987) review is a report by Roy et al. pramine was binding to an allosteric regulator of the (19871, who found no change in any aspect of serotonin serotonin transporter, rather than competing directly uptake in 51 depressed patients. This was also true with the binding of serotonin to its carrier site. The when the patients were analyzed according to subtype of presence of an allosteric regulator then led to the search depression and past history of attempted suicide. These for an endogenous antidepressant substance (an enthe two modes of the control population. While CSF 5-HIAA may correlate with certain components of depression, it does not appear to consistently covary with depressed mood, and thus far does not appear to be predictive of response to various ADTs.

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docoid) for the imipramine “receptor,” by analogy with the endocoids discovered shortly after identification of the morphine receptor (Sette et al., 1983; Barbaccia et al., 1983; Langer et al., 1984). Psychiatric depression might result from abnormal metabolism of the putative endogenous antidepressant substance. However, the present evidence suggests that this putative endocoid is no longer predicted because the high-affinity, proteinaceous, sodium-dependent, serotonin-sensitive L3H1imipramine-binding site appears identical to the serotonin recognition site of the serotonin transporter. Specifically, the inhibition of serotonin uptake by imipramine is competitive in nature (Marcusson et al., 1986), and the displacement of [3Hlimipramine binding by serotonin is also competitive (Humphreys et al., 1988). In platelets, it appears that a significant fraction of the desipramine displaceable [3Hlimipramine binding is not to the serotonin transporter, as 30% of that binding is not sodium dependent (Hrdina et al., 1989). Furthermore, if L3H1imipraminewere labeling the serotonin transporter, changes in the V,, for uptake should be paralleled by changes in B, for binding. Poirier et al. (1986) did detect this relationship, with reduced r3H]imiprarninebinding in depressed patients that normalized after ADT. Similar results were obtained by Wagner et al. (1987). Two additional studies report reduced platelet [3Hlimipramine binding in depressives, similar t o the studies measuring uptake directly (Innis et al., 1987; Roy et al., 1987). However, other reports have found that L3H]imipraminebinding is not modified in depression (Mellerup et al., 1982; Muscettola et al., 1984; Katona et al., 1986; Egrise et al., 19861, nor is it even correlated with the severity of depression (Carstens et al., 1986; Braddock et al., 1986; Georgatos et al., 1987). Given the recognition that i3HIimipramine binding displaced by other tricyclic antidepressants is heterogeneous (Humphreys et al., 1988; Graham et al., 19891, it would seem appropriate to repeat many of these studies using more selective ligands that do not label multiple sites when used properly, such as [3H]paroxetine(Backstrom et al., 1989). Other changes in platelets with depression In addition to serotonin uptake, platelets respond normally to serotonin release with a shape change leading to aggregation during the normal clotting response. The density (B,=) of S-2 (5HT-2) receptors mediating this change is increased in depressed patients (Biegon et al., 1987;Arora and Meltzer, 1989),but this increase is not correlated with the severity of depression, suicidal tendencies, or serotonin uptake. Biegon et al. (1987)report that this elevation returns to normal levels after ADT. Brusov et al. (1989)found that the platelet shape change response was more sensitive to serotonin in depressives, and this sensitivity returned to normal after ADT, totally consistent with the binding data. Conversely, Cowen et al. (1987) found no

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differences in S-2 receptor density in the platelets of depressed patients. Moreover, these authors and Grahame-Smith et al. (1988) found that ADT increased the density of S-2 sites. Clearly, more research is required, carefully comparing different ADTs to resolve these divergent results. Two other isolated findings on human platelets relate changes in depression to the serotonin system. Sarrias et al. (1987) report that depression is associated with decreased concentrations of serotonin in both platelets and plasma, and the platelet serotonin levels are further reduced by ADT, confirming earlier work by Coppen et al. (1976) and Le Quan-Bui et al. (1983). Quintana (1988) reports that platelet MA0 activity is massively elevated in depression (250%),and gradually returns to normal after 2 months of imipramine therapy. This report references additional studies of MA0 activity during the 1970s that both confirm and deny this change in depression. The significance of these findings is uncertain. Once again, many of the studies of serotonergic markers in platelets act as state variables for depression, yet none of these changes is diagnostic. Convincing correlations with severity of specific components of depression are lacking. Furthermore, the relationship of these changes in platelets to CNS serotonin function remains enigmatic. Neuroendocrine effects of serotonergic agonists Another window on CNS serotonin function that can be evaluated in living subjects is neuroendocrine responses t o exogenous serotonin agonists. Presumably, changes in the typical responses to these agonists indicate changes in CNS serotonergic receptor sensitivity or, in some cases, nerve activity. One response that has been examined by several groups is the increase in plasma prolactin produced by serotonin agonists. Some of these studies have used the precursor amino acid tryptophan. Heninger et al. (1984) described lower tryptophan-induced elevations of prolactin in depressed patients compared to controls. Cowen and Charig (1987) found a similar diminished response in depressives that had not exhibited weight loss. Price et al. (1990) report that this reduced neuroendocrine response is specific to depressives that were not melancholic; melancholic depressives had normal tryptophan-induced prolactin elevations. A similar effect was reported by Koyama and Meltzer (19861,but some of this effect was attributed to the lower endogenous plasma tryptophan concentration in the depressed patients, Partial support for these data with tryptophan derives from a study with another indirect serotonin agonist, fenfluramine. Fenfluramine releases serotonin from synaptic terminals and may also block its reuptake. Coccaro et al. (1989) found the prolactin response t o fenfluramine to be blunted in patients with personality disorder, but not depression. There was a good correlation between the blunting of

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the response and a history of suicide attempts in depressed and personality disordered patients, and a correlation with impulsive aggression in the patients with personality disorder. Siever et al. (1984a) had earlier found a significant reduction in the fenfluramine-induced prolactin response in depressed patients. Some, but not all, ADTs appear to restore the prolactin response to tryptophan to normal levels in depressed patients, but the time course of these effects is complex (reviewed in Price et al., 1990). Meltzer et al. (1984) reported that another serotonin precursor, 5-HTP, produced greater elevations of ACTH and serum cortisol in depressed patients than controls. This enhanced sensitivity was correlated with reduced CSF 5-HIAA in the depressed patients (Koyama et al., 1987). Treatment with TCAs normalized the response. An S-1a agonist, ipsapirone normally reduces body temperature via activation of the serotonergic autoreceptors (this response disappears in rats with lesions of the serotonin system). Lesch et al. (1990)found that the hypothermic response to ipsaperone in depressed patients was reduced compared with controls. Treatment with the TCA amitriptyline further diminished the response, suggesting that unlike the other neuroendocrine changes, this response was a trait variable rather than a state variable. In summary, all three types of responses suggest disturbance in the sensitivity of the serotonin system to pharmacologic intervention. In some instances, the responses are attenuated, while in others they are reduced, yet a different mechanism may explain this divergence. It is not certain that the serotonergic systems involved in these hypothalamic responses accurately reflect the brain serotonin systems that might be involved in depression any more than the platelet serotonin systems. Nonetheless, these data point to serotonergic dysfunction within the CNS of depressives.

Studies in postmortem tissue samples A more direct window on serotonin function in the CNS, although necessarily static (rather than dynamic) in nature are neurochemical measurements from postmortem samples. Early studies during the 1960s and early 1970s described reductions in serotonin and 5H I M in the brain stem of suicide victims and depressives who had died from natural causes, with no change detected in the degradative enzyme MA0 (reviewed in Stanley et al., 1986). More recent studies have focused on binding sites for various receptors in the serotonin system. Initial reports found an increase in the S-2 (5HT-2) receptor in the frontal cortex of suicide victims (Stanley and Mann, 1983; Mann et al., 1986). S-1 binding sites did not change. This was partially confirmed by McKeith et al. (19871,who reported a 30%increase in S-2 (5HT-2)sites

in frontal cortex samples from depressives who died from natural causes which was not statistically significant. This study also reported nonsignificant increases of 50% for S-1 sites, and 50% decreases in 5-HIM. The only significant finding in this study was that depressives who died while receiving ADTs had higher 5-HIM than depressives withdrawn from ADTs. However, a number of reports dispute these findings. Owen et al. (1983) observed a nonsignificant decline in S-2 sites in suicide victims. Cheetham et al. (1988a) found a significant reduction in S-2 binding in the hippocampus from suicides who had not received ADTs, but no change in those who had received ADTs. These authors found no change in S-2 binding with or without ADTs in frontal, temporal and occipital cortices. Gross-Isseroff et al. (19901, in a careful study using both autoradiographic and in vitro solution methods, reported a 40% decline in the S-2 receptor in both frontal cortex and hippocampus of young suicide victims, but no change in the older suicides. Stanley and Mann (1983)) Cheetham et al. (1988a,b),and Gross-Isseroff et al. (1990) all reported a decline in the S-2 sites with age in the frontal cortex, described in greater detail by Marcusson et al. (1984). Several groups have also reported on 13Hlimipramine binding sites in suicide or depression, but these data are subject to the same caveats as described for platelet I3H]irnipraminebinding. Stanley et al. (1982) described a reduction in [3H]imipramine binding in the frontal cortex of suicides, as did Gross-Isseroff et al. (19891, but the latter workers detected an increase in these sites in the hippocampus. In depressed patients who had died from natural causes, Perry et al. (1983) detected a decline in r3H1imipramine binding in the occipital cortex, but Ferrier et al. (1986) found no change in the frontal cortex using the more selective ligand [3H]paroxetine. In summary, the loss of brain stem serotonin in suicide victims is indicative of some decline in the serotonergic activity in the cell bodies of the serotonin system, but the possible influence of various premortem drugs on these measures must be considered. The initial reports of increased S-2 (and Beta-adrenergic receptors) in suicides were intriguing because one action of antidepressant drugs is to decrease these binding sites in animal models (see below). Thus, it made sense that these sites might be elevated to cause depressive symptoms, and their reduction by ADTs would underlie recovery. Unfortunately, the recent data fail to confirm these changes, and additional data with careful analysis of drug influences and types of depression premortem are definitely required to resolve this issue. The decline in imipramine binding would imply that there may be some loss of serotonergic terminals in depressives committing suicide, but the absence of any difference with paroxetine, and the aforementioned heterogeneity in most [3H]imipramineassays complicates interpretation of these data. In short, these data are a valuable begin-

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ning, but more studies will be required before definitive statements can be made. Antidepressant effects on the neurochemistry of animals (Table 111) While the acute effects of ADTs all seem to impact in one fashion or another on the serotonin system, it is important to realize that these short-term actions are inadequate to cause a therapeutic response. All ADTs require repeated administration before the acceleration of recovery from the depressive symptoms becomes manifest, suggesting that the drugs are inducing some slowly developing structural or genomic change. It is important to realize that these changes need not occur in the systems that the drugs are acting upon for their short-term responses. Hence, a significant amount of research energy has focused on the long-term effects of repeated administration of these therapies upon brain chemistry in animal models, almost exclusively in rodents, and primarily in rats. As mentioned above, one caveat concerning these results is that the effects of these drugs may be different in depressed and nondepressed humans due to differences in the underlying neurochemistry. As few studies have examined the neurochemical effects of these drugs in animal models of depression, and there is some possibility that the transmitter interaction in humans and rats may be somehow different, these results must be considered as suggestive rather definitive of the effects of these drugs in depressed humans. Nonetheless, there are recent data that all the ADTs, when administered to humans, share a common long-term effect in the rat CNS, and that is to reorganize the serotonin system so as to potentiate the activity a t serotonergic synapses. Chemical and behavioral changes at 5HT-2 receptors One of the most consistent effects of long-term treatment with TCAs or MAOIs is a down-regulation in the number of binding sites €or the S-2 (5HT-2) receptor (reviewed in Sugrue, 1983; Heninger and Charney, 1987; Cowen, 1990). Most of the SUBs also produce this decline in S-2 binding sites (Wamsley et al., 1987; Nelson et al., 19891, although occasional studies fail to detect down-regulation with some SUBs (Cross and Horton, 1987). ECT, however, has been consistently demonstrated to have the opposite effect of the other ADTs; it increases the number of S-2 binding sites (see Lerer, 1987), suggesting that this is unlikely to be the primary therapeutic action ofADTs. Recent studies also question the universality of the S-2 regulation with ADTs. Schoups et al. (1986) and Schoups and Potter (1988) failed to detect decreased S-2 binding in rabbit brain with a variety of ADTs, yet did detect these changes in rat frontal cortex. Biegon and Israeli (1987) examined the S-2 receptor elevation to ECT in male and

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female rats and found the expected increase in binding in male rats but very little change in female rats. The major behavioral measure of S-2 receptor function is the head-twitch response produced in mice receiving certain serotonergic agonists. This response is blocked by S-2 antagonists but not other serotonergic antagonists. The behavioral results accord well with the receptor studies; TCAs, MAOIs and most SUBS reduce this behavior, while ECT increases it (summarized in Grahame-Smith, 1989; Cowen, 1990). Recently, Godfrey et al. (1988)found that TCA treatment decreased and ECT treatment increased the head-twitch response, as expected. However, when the S-2receptor activation of phosphoinositide metabolism was studied in vitro, little if any change was observed. While perplexing, it is plausible that those S-2 sites linked to phosphoinositide metabolism are not those regulated by chronic antidepressants. Future research relating the behavioral responses to neurochemical measurements in the same animals is called for. In summary, the decrease in S-2 (5HT-2) binding in response to most ADTs is a robust and consistent finding at both the chemical and behavioral levels. However, the opposite reaction to a very effective ADT (ECT), and the apparent species and gender specificity of this response suggest it is unlikely that this is the major therapeutic action of ADTs. In fact, assuming that the problem in depression is impaired serotonergic activity, this change should exacerbate the symptoms, not ameliorate them. Nonetheless, interactions with other receptors and transmitter systems could easily be invoked to explain this theoretical problem. Down-regulation of S-2 receptors remains a benchmark that identifies potential antidepressant activity of compounds in preclinical stages of development. Chemical and behavioral changes at 5HT-1 receptors One difficulty in evaluating the past research on the S-1 receptor is that it is widely accepted that this binding site (defined by [3Hlserotonin binding) is heterogenous with as many as five subtypes (S-la through S-le; a.k.a. 5-HT1, through 5-HT1,) labeled using the standard conditions of most studies (Green and Maayani, 1987; Leonhardt et al., 1989). Most studies of S-1 aggregate binding fail to detect differences following long-termADT administration (summarized in Heninger and Charney, 19871, although some MAOIs may decrease this binding site (see Cowen, 1990). However, the SUB fluoxetine is reported to decrease S-1 binding (Wamsley et al., 1987) while the SUB paroxetine does not (Nelson et al., 1989). In the first studies of specific S-la binding following ADTs, Welner et al. (1989) reported that TCAs produce a n increased number of sites in the terminal fields (hippocampus), but no change in the cell body regions (dorsal raphe), while SUBs and S-la agonists produce no change in the terminal fields,

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Using these measures, two patterns of changes emerge following ADT treatments. First, TCAs and ECT have no long-term effects on the basal firing rate or autoreceptor inhibition of the serotonergic neuron firing rate. However, stimulation of the serotonin neurons or iontophoretic application of serotonergic agonists produces greater postsynaptic responses in hippocampus and several other brain regions, suggesting increased sensitivity of postsynaptic serotonin receptors. A second pattern seen with MAOIs, SUBs and S-la agonists involves a short-term inhibition of the firing rate of serotonergic neurons (due to enhanced availability of serotonin at the somatodendritic autoreceptor), followed by recovery to normal firing rates within 2 weeks. After long-term administration of ADTs, the capacity of serotonin agonists to reduce this firing rate is impaired, suggesting that the somatodendritic autoreceptors have desensitized, accounting for the return to normal firing rates after 2 weeks in spite of elevated extracellular serotonin. The postsynaptic responsiveness to iontophoresed serotonin is unchanged (implying normal postsynaptic receptor sensitivity), but the postsynaptic responsiveness to stimulation of the raphe system is elevated for MAOIs and SUBS,but not S-la agonists. Additional data suggest that the enhanced responsiveness to MAOTs and SUBs is due to enhanced release of serotonin per impulse caused by desensitization of the terminal autoreceptor. Enhanced serotonergic activity with the S-la agonists would be mediated by direct activation of normosensitive postsynaptic serotonin receptors, when summed with normal amounts of activity in the serotonergic neurons (due to somatodendritic autoreceptor desensitization). Thus, with all ADTs, there is a gradual development of increased activity in Electrophysiological analyses of the the serotonin system as a common endpoint, although serotonin system the mechanisms by which this enhancement is achieved In several impressive reviews, Blier et al. (1987; 1988; are slightly different for the different classes of ADTs. The arguments presented in the Blier et al. reviews 1990)summarize the evidence concerning the short and long-term effects of ADTs on the pre- and postsynaptic are compelling, but there are some potential contradicelectrophysiological properties of serotonin neurons. tions. First, the reduction of S-2 receptor density with The following is a summary of these data, and the all ADTs except ECT (and possibly S-la agonists) reader is referred to these other reviews for details. should decrease the postsynaptic sensitivity a t these Several parameters of serotonergic function can be synapses and, presumably, serotonergic transmission. characterized electrophysiologically. First, the firing Second, a recent study by Beck and Halloran (1989) rate of serotonergic neurons in the raphe nuclei of the failed t o confirm the enhanced postsynaptic sensitivity brain stem can be monitored. Second, the activity of the of hippocampal neurons to serotonin following TCA somatodendritic autoreceptor (an S-la receptor) can be administration. Moreover, the behavioral responsiveevaluated by monitoring the decrease in firing rate ness to serotonergic agonists following various ADTs is produced by the administration of serotonergic ago- typically reduced, not increased as predicted by the nists. Third, the sensitivity of postsynaptic serotonin increased postsynaptic sensitivity produced by TCAs. receptors can be monitored by measuring the electro- While these discrepancies can be partially explained by physiological responses of neurons in the serotonin the decreased autoreceptor sensitivity produced by terminal fields following iontophoretic application of some treatments, certain inconsistencies remain unexserotonin agonists. Finally, the overall efficacy of sero- plained. Perhaps a detailed resolution of the serotonin tonergic activity can be evaluated by monitoring these receptor subtypes underlying the behavioral and elecpostsynaptic responses following stimulation of the se- trophysiological responses will explain these apparent rotonergic neurons in the raphe nuclei. contradictions. and decreased binding in the cell body regions. These data are consistent with the electrophysiological data described in the next section. There are two behavioral responses that, based on their pharmacoiogy, are believed to be mediated by S-1 receptors. One is referred to as the “serotonin syndrome”, which includes forepaw treading and hindlimb abduction, which appears to be mediated by postsynaptic S-1 receptors (Tricklebank, 1985). The other response is a hypothermic reaction to a selective S-la receptor agonist. This hypothermia appears to reflect activity at autoreceptors on the serotonin cell bodies and/or terminals as the response is abolished following lesions of the serotonin system (Goodwin et al., 1985). Unlike the responses of the binding sites, both S-1 receptor-mediated behaviors are attenuated by repeated administration of TCAs, MAOIs and ECT (summarized in Grahame-Smith, 1989; Cowen, 1990). Another measure of serotonin autoreceptor function, the inhibition of serotonin release in vitro by serotonin application, also is reduced following ADT treatment (Wamsley et a]., 1987). In summary, while aggregate S-1 receptor number does not appear consistently modified by ADTs, data are emerging from behavioral and more specific chemical analyses that down-regulation of the serotonin autoreceptors may occur with certain ADTs. A decrease in autoreceptor function on serotonergic neurons should enhance serotonergic transmission by either increasing the impulse rate (somatodendritic autoreceptor) or the release of serotonin per impulse (terminal autoreceptor). The delineation of changes in specific subclasses of S-1sites is an important area for future analyses.

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To summarize, the studies in animals of the long-term changes in the serotonin system following repeated exposure to ADTs have generated some insight into the mechanism of action of these treatments. Most have significant effects on one or more components of the serotonin system whether measured chemically, behaviorally, or electrophysiologically.Unfortunately, not all of the measured changes are consistent across the different fields, and for some measures even within fields. Future studies may focus on combined analysis of chemical, behavioral, and electrophysiological measures in the same group of animals using the same treatments. Moreover, the chemical measurements are becoming increasingly sophisticated as the myriad of serotonin receptor subtypes become better defined pharmacologically. This is a ripe area for interdisciplinary collaboration within neuroscience.

Conclusions, problems, and future directions This section has described most of the evidence for a role of the serotonergic system in the etiology and therapy of depression. Three major classes of evidence have been presented: (1)the acute effects of most ADTs modify serotonergic transmission; (2) peripherally accessible and postmortem measurements of CNS function that indicate the serotonin system is impaired in depressives; and (3) the long-term effects of ADTs in animals studies point toward some enhancement of serotonergic activity. However, for all classes of evidence, there are inconsistencies in the primary data, and contradictions concerning the directions of the effects (e.g.,loss of S-2 receptors but enhanced postsynaptic responsiveness electrophysiologically). But perhaps most important is the fact that all the evidence gathered thus far is circumstantial. It is true for all ADTs that there is a lag period between the initiation of therapy and the development of therapeutic responses. Hence, the acute effects of these ADTs cannot be the sole explanation for their efficacy. The problem with the actions of the ADTs is that therapy and etiologyneed not be synonymous. The development of arteriosclerosis has little to do with the therapies for hypertension, yet arteriosclerosis undoubtedly contributes to isolated systolic hypertension found with increasing age. The studies in human depressed populations necessarily measure indirect reflections of CNS serotonin activity. The biochemical measurements in depressed humans are so far limited to blood, CSF, or neuroendocrine parameters. The relationship among the CSF, hypothalamic, and blood platelet changes observed in depression and the activity of the serotonergic system in higher regions of the CNS can never be certain. Postmortem studies of CNS chemistry are subject to the confounds of illness, variable psychoactive drug exposures, postmortem autolysis, and the difficulty in assessing the same individ-

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ual at several time points. Finally, the long-term effects of ADTs on the serotonin system in animals are complicated by the possibility that the effects of these treatments are different in depressed versus normal individuals, and the possibility that the long-term responses to the ADTs in rats may be different than those in humans. These caveats not withstanding, this reviewer feels that when taken as a whole, the evidence strongly supports the basic hypothesis mentioned in the introduction of this chapter: that depression results in part from a deficiency in serotonergic activity, and one common long-term action of ADTs is an enhancement of serotonergic activity. Recent technologicaldevelopments should allow more direct tests of the serotonin hypothesis of depression. Perhaps foremost among these has been the development of Positron Emission Tomographic (PET) measurements of receptors and nerve terminals in living humans. The major advantages of PET analysis is that neurochemical parameters can be measured in a variety of brain regions in drug-naive depressives, and contrasted with normal controls. The individual's response to ADTs can then be monitored and subsequent scans used to determine the CNS responses to these therapies. In addition to the S-2 (5HT-2)receptor, other probes can be developed for the subclasses of S-l(5HT-1)receptors, and the density of serotonin terminals could be estimated from injections of positron-labeled 5-HTP, by analogy to the estimate of dopaminergic terminals with labeled L-DOPAin parkinsonians (Calne et al., 1985). Such studies would escape the unavoidable complications of postmortem tissue analysis, the major one being that the patient must have died, often from a protracted illness, and the interpretive difficulties with peripheral measures of CNS function. A second technological advance that would add to the animal literature on the long-term effects of ADTs is in vivo microdialysis. This technology permits repeated estimates of extracellular neurotransmitter levels in freely behaving animals, and its utility has been convincingly demonstrated in studies of chronic amphetamine and cocaine administration (Robinson et al., 1988; Kalivas and Duffy, 1990). The manipulation of extracellular serotonin concentration by lesions and autoreceptor agonist administration has already been detected using this technique (Sharp et al., 1989). A final area where new insights will develop is the examination of serotonergic changes in animal models of depression. A number of models have now been developed which respond favorably to ADTs, and the study of basal differences in serotonin chemistry, electrophysiology and behavior, as well as the effects of ADTs in the reversal of these changes will avoid one major criticism of the studies describing the long-term effects of ADTs in normal animals. To conclude, the serotonin hypothesis of the etiology and therapy of depression has endured for almost a

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quarter century. A sizable body of literature, not always consistent, has accumulated supporting various components of this hypothesis. It is probably nai've to assume that a disorder as complex and multifaceted as human major depressive disorder will ultimately be understood as a dysfunction of a single neurotransmitter system. The complex interactions of brain chemistry preclude the likelihood of such a simplistic interpretation, and strong arguments exist for the involvement of other neurotransmitter system dysfunctions, in addition to serotonin (see other sections in this review). Nonetheless, this reviewer is confident that the growing evidence from independent sources strongly argues for a major role ofthe serotonin system in both the etiology of and therapeutic interventions into the widespread disorder commonly known as depression.

NORADRENERGIC/SEROTONERGIC INTERACTIONS (S. Caldecott-Hazard) An abundance of data suggests that noradrenergic and serotonergic systems in the brain may be involved in the pathophysiology of depression. Furthermore, these neurotransmitter systems have been implicated in the therapeutic actions of tricyclic and monoamine oxidase inhibitor (MAOI) antidepressant drugs. , This section reviews behavioral, biochemical, and electrophysiological evidence that the noradrenergic and serotonergic systems can be simultaneously affected by individual antidepressant drugs. We also describe some of the anatomical and biochemical mechanisms by which these drugs may affect both systems, thus establishing a noradrenergidserotonergic link through which abnormalities or therapies might be manifested. The data presented in this section are examples that support more general statements and that stress the most recent information on the topic. Evidence that both transmitter systems are affected by individual antidepressants Behavioral data A number of behaviors or physiological changes have been induced in rodents by the injection of noradrenergic or serotonergic agonists. Certain antidepressant drugs have been tested for their effects on both sets of behaviors (Heninger and Charney 1987). For example, clonidine or apomorphine stimulate locomotor activity and aggression in rats. The activity of clonidine is thought to be via activation of postsynaptic Alpha-2 adrenergic receptors, and both noradrenergic and dopaminergic receptors are involved in the action of apomorphine. Long-term administration of tricyclic antidepressants, such as imipramine, amitriptyline, o r desipramine, increases both the activity and aggression produced by clonidine or apomorphine (Maj et al., 1979a,b). These results coincide with reports that the same antidepressants cause Alpha-adrenergic receptor supersensitivity (Menkes et al., 1980; Menkes and Aghajanian, 1981).

Imipramine, amitriptyline, and desipramine also affect serotonergic behaviors. The serotonin-1 receptor agonist, 5-MeODMT, causes head twitching in mice, exacerbated by long-term administration of these antidepressants (Friedman and Dallob, 1979). When 5hydroxtryptamine is given to chickens, it causes sleep, which is prolonged by these antidepressants (Jones, 1980). In addition, these behavioral data coincide with electrophysiologicalfindings of enhanced sensitivity of postsynaptic serotonin receptors following imipramine or amitriptyline (DeMontigny and Aghajanian, 1978; Menkes et al., 1980; Menkes and Aghajanian, 1981). Another antidepressant, mianserin, also increases the aggression produced by clonidine (Maj et al., 1979a,b). Its mechanism of action is thought to be via the blockade of presynaptic Alpha-2 receptors (Blackwell, 1987),which results in a net increase in presynaptic norepinephrine release. However, the drug also enhances head weaving and forepaw treading produced by the serotonin precursor, 5-hydroxytryptophan (5HTP) (Mogilnicka and Klimek, 1979). Two other responses, drinking induced by the Beta-adrenergic agonist isoproterenol, and hypothennia, induced by the serotonin-1 receptor agonist 8-OH-DPAT,were decreased by mianserin (Goldstein et al., 1985; Goodwin et al., 1985). Although the mechanisms underlying the effects of mianserin on the latter two behaviors are not understood, the drug clearly affects both transmitter systems. Other experimental antidepressants that also affect noradrenergic and serotonergic systems include salbutamol. This drug is a Beta-adrenergic agonist that coincidentally increases the head weaving and forepaw treading induced by 5-hydroxytryptophan or L-tryptophan in rats (Ortmann et al., 1981; Cowen et al., 1982). By contrast, propranolol, which is capable of producing depression in humans (PDR, 19901,is a Betareceptor antagonist; it decreases 5-hydroxytryptophaninduced behaviors in rats (Goodwin and Green, 1985; Green and Grahame-Smith, 1976). Biochemical data (Table 111) Brain concentrations of transmitters and metabolites. Many individual antidepressants increase brain concentrations of both norepinephrine and serotonin. For example, the tricyclic antidepressants amitriptyline, imipramine, protriptyline, nortriptyline, and amoxepine block the reuptake of both norepinephrine and serotonin, thereby increasing concentrations of these transmitters (Bryant and Brown, 1986). Monoamine oxidase inhibitors (MAOIs) such as clorgyline increase concentrations of norepinephrine and serotonin by inhibiting the enzyme that catabolizes both transmitters (Campbell et al., 1979). However, as is now well known, the time course of increased transmitter concentrations in animals and the onset of clinical effectiveness in humans (using tricyclic antidepressants or MAOIs) do not necessarily coincide. Thus, the clinical relevance of

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antidepressant induced changes in brain norepinephrine and serotonin concentrations is questionable. Various studies have also reported that tricyclic antidepressants, such as amitriptyline, imipramine, and clomipramine, the atypical antidepressant zimelidine, and the MAOI clorgyline, each decrease both the norepinephrine and serotonin metabolites, MHPG and 5-HIAA, in the urine or CSF of depressed patients (Asberget al., 1975; Beckmann and Goodwin, 1975;Post and Goodwin, 1974; Potter et al., 1985; Siwers et al., 1976). However, increases or no change in noradrenergic and serotonergic metabolites have also been reported (Charney et al., 1981).Furthermore, decreases in these metabolite concentrations often do not correlate with clinical responses to the drugs (Charney et al., 1981). For example, Maas et al. (1972) found that only patients who failed to respond clinically to imipramine showed decreases in urinary MHPG levels. Thus, the clinical relevance of antidepressant-induced changes in norepinephrine and serotonin metabolites is also questionable. Receptors and second messengers. When given chronically, many individual antidepressants alter the density of various subtypes of both noradrenergic and serotonergic receptors. For example, tricyclics, such as imipramine, amitriptyline, desipramine; MAOIs, such as pargyline; and atypicals, such as iprindole, each reduce the density of Beta-adrenergic and 5HT-2 (serotonin) receptors, and they block the stimulation of cyclic adenosine monophosphate (CAMP)by norepinephrine (Charney et al., 1981; Heninger and Charney, 1987; Fuxe et al., 1982; Tsukamoto et al., 1982; Sulser and Mishra, 1982). These effects occur in most areas of the brain where the drugs have been tested, for example, the cerebral cortex, hippocampus, and striatum. Some reports indicate that desipramine and amitriptyline have even broader effects such as also decreasing the number of 5HT-1 receptors and increasing the density of Alpha-2 adrenergic receptors in whole brain, limbic forebrain, or cerebral cortex (Charney et al., 1981). Some MAOIs (clorgyline, pargyline, nialamide) have also been reported to decrease 5HT-1 receptor densities in cerebral cortex (Frazer and Luchi 1982; Charney et al., 1981; Savage, 1979). Even some selective serotonin uptake inhibitors, such as fluvoxamine and sertraline, have been found to decrease the densities of Betaadrenergic receptors (Sulser, 1989). However, these data are not without controversy; desipramine and amitriptyline have also been reported to be without effects on Alpha-adrenergic and 5HT-1 receptors in cerebral cortex (Charney et al., 1981). In addition, Welner et al. (1989) recently reported that amitriptyline increased the density of 5HT-1A receptors.

applied agonists (Blier et al., 1990; Charney et al., 1981). Specifically, the chronic administration of the tricyclics imipramine, amitriptyline, desipramine, and the atypical antidepressant iprindole each increase neural firing t o norepinephrine and to serotonin in the dorsal lateral geniculate nucleus (Menkes and Aghajanian, 1981). In the facial nucleus and amygdala, iprindole also increases neural firing to agonists of both transmitter systems (Menkes et al., 1980; Wang and Aghajanian, 1980). While these adrenergic effects are thought to be via Alpha-1 receptors, desipramine has also been reported to decrease neural firing that may be mediated by Beta-receptors in the cingulate cortex, locus coeruleus and cerebellum (Olpe and Schellenberg, 1980; Schultz et al., 1981; McMillen et al., 1980; Charney et al., 1981). The administration of MAOIs such as clorgyline or phenelzine decreases the firing rate of postsynaptic serotonin-containing neurons in the dorsal raphe nucleus and of norepinephrine-containing neurons in the locus coeruleus (Blier et al., 1990). These effects are thought to be caused by the increased synaptic availability of serotonin or norepinephrine, respectively. The increase in transmitters is then thought to stimulate autoreceptor-mediated inhibition of cell firing. However, serotonin autoreceptors become desensitized with chronic MA01 use, and raphe neuron firing recovers to predrug levels (Blier et al., 1990). Thus, the importance of these electrophysiological changes for MAOI effectiveness is unclear. It is interesting to note that in receptor binding and electrophysiological studies, the same drug may have different effects depending on the brain region studied. Also, the receptor and electrophysiological data did not always coincide. For example, the tricyclic imipramine has been reported to decrease serotonin-1 receptor binding in the hippocampus (Maggi et al., 1980b), but to increase hippocampal neuron sensitivities to serotonin (De Montigny and Aghajanian, 1978). In summary, while there are some inconsistencies in the data, there is also much evidence from behavioral, biochemical, and electrophysiological studies supporting the dual effects of antidepressant drugs on noradrenergic and serotonergic systems. Furthermore, these dual-action antidepressants belong to a variety of drug subtypes: tricyclics, MAOIs, atypicals, and specific receptor agonists or uptake blockers. The next section will provide evidence for mechanisms by which these drugs may affect both the noradrenergic and serotonergic systems.

Electrophysiological data Electrical recordings of nerve action potentials have demonstrated that antidepressant drugs can modify the firing rate of postsynaptic neurons to iontophoretically

On the basis of much of the antidepressant literature, one could construct hypotheses that would propose how certain antidepressant drugs act on both noradrenergic and serotonergic systems in the brain. One hypothesis

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could involve parallel mechanisms of change in noradrenergic and serotonergic systems. Thus, antidepressants would act on each transmitter system independently, but at the same time. The involvement of both transmitter systems would be necessary for clinical efficacy. A second hypothesis could involve series mechanisms of change whereby an antidepressant would interact directly with only one of the two transmitter systems. However, the neurons of the two systems would have anatomical and biochemical connections; thus, both noradrenergic and serotonergic systems would be involved in the final effect of the drug. Recently, new data have indicated that revisions would be needed in these proposed hypotheses. Some antidepressant drugs thought to act via parallel mechanisms might actually work via series mechanisms. Also, some antidepressants that were thought to act via series mechanisms might actually work through only one transmitter system. These data are discussed in more detail later in this section.

Parallel mechanisms Drugs that appear to act via these mechanisms include MAOIs, which inhibit the enzyme responsible for catabolizing both norepinephrine and serotonin. Thus both transmitter systems are affected simultaneously. Other drugs in the parallel mechanism group may include those capable of interacting simultaneously with several different receptors or binding sites. For example, certain tricyclics, such as amitriptyline, imipramine, nortriptyline, and amoxepine, bind to both serotonergic and noradrenergic reuptake sites (Bryant and Brown, 1986). These effects lead to increased norepinephrine and serotonin concentrations and perhaps to the more clinically relevant receptor changes as well. With some of these tricyclics, binding to the reuptake sites of one system may be stronger than to the other system. Also some tricyclics that have high affinities for both noradrenergic and serotonergic systems (amitriptyline and imipramine) are metabolized to drugs that preferentially block reuptake in the noradrenergic system (Blier et al., 1990).Thus, although both transmitter systems may be altered, the relative degree of alteration for the two systems may vary. Additional data exist that are relevant to the multiple binding properties of certain antidepressants and that support the parallel mechanism hypothesis. The tricyclics doxepin, amitriptyline, and nortriptyline strongly block both serotonin-2 and Alpha-1 adrenergic receptors (Peroutka and Snyder, 1980b). However, it is not clear whether these blocking properties are involved in the mechanisms of antidepressant action. On the other hand, the mechanism of action of mianserin is thought to include presynaptic Alpha-2 receptor antagonism (Blackwell, 1987); the drug also blocks serotonin-2 receptors (Peroutka and Snyder, 1980a).

Series mechanisms Antidepressant drugs that might act via these mechanisms include serotonin uptake inhibitors (fluvoxamine and sertraline) that are highly specific for the serotonergic system. Interestingly, these drugs also have been reported to decrease Beta-receptor densities and to desensitize the Beta-receptor coupled adenylate cyclase system (Sulser, 1989). Since the mechanism of these changes in Beta-receptors does not appear to be via direct actions of the drugs on the receptors, a series interaction of serotonergic and adrenergic neurons is likely. Other antidepressants that might act via these mechanisms include specific Beta-adrenergic agonists, such as salbutamol. These drugs are also reported to increase 5HTP-induced behaviors (Ortman et al., 1981). Since the primary effect of the Beta-agonists is on the stimulation of Beta-receptors, the secondary effects (enhancing 5HTP behaviors) may be due to anatomical and biochemical connections between the two transmitter systems. Both desipramine and electroconvulsive shock have been reported to alter the densities of serotonin and Beta-adrenergic receptors (Charney et al., 1981). Furthermore, a number of studies initially reported that desipramine and ECS each required the presence of intact serotonergic neurons in order to down regulate Beta-adrenergic receptors (Brunello et al., 1982; Janowsky et al., 1982; Nimgaonkar, 1985; Sulser and Saunders-Bush, 1987). One interpretation of these data would imply a series mechanism involving both serotonergic and noradrenergic neurons in the down-regulation of Beta-receptors. However, as discussed later, recent data alter this interpretation. Evidence that series connections between noradrenergic and serotonergic systems exists is given below. The data are grouped according to anatomical or biochemical studies. Anatomical connections. Anatomical connections between the noradrenergic and serotonergic systems have been known for many years. Dahlstrom and Fuxe (1964) used a fluorescence method to demonstrate that catecholamine-containing axons innervate serotonin cell bodies in the raphe nuclei (Dahlstrom and Fuxe, 1964). More recent studies, using electron microscope autoradiography, confirmed these findings (Baraban and Aghajanian, 1981).Pickel et al. (1975) used immunohistochemical techniques to determine that the noradrenergic cell bodies in the locus coeruleus receive important serotonergic inputs (Pickel et al., 1975). This finding was confirmed using autoradiographic techniques (Leger and Descarries, 1978). Biochemical connections. Norepinephrine synapses onto serotonergic neurons. Studies of this topic can be further subdivided into noradrenergic inputs onto serotonergic cell bodies or dendrites, and noradrenergic inputs onto serotonergic terminals. The former studies reported that Alpha-1 adrenergic receptors and possibly

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also Beta-adrenergic receptors are present on postsynaptic, serotonergic cells, implying noradrenergic inputs onto those cells. Specifically, iontophoretically applied Alpha-1-antagonists inhibited the firing of serotonergic cells in the raphe nuclei, and Alpha-1 agonists restored the cell firing. It was postulated that “norepinephrine terminals, present in the dorsal raphe, mediate a tonically active adrenergic influence on which the firing of serotonergic cells depend (Baraban and Aghajanian, 1980). Another study showed that the systemic administration of the norepinephrine releasing agent IBMX caused an increase in serotonin turnover in the terminal fields of the dorsal and median raphe system (the neocortex and striatum, and hippocampus, respectively) (Reinhard et al., 1983). Coadministration of the Beta-receptor antagonist propranolol, or lesions of noradrenergic neurons (via the neurotoxin 6-OHDA) blocked the serotonergic effect of IBMX. It was hypothesized that the release of norepinephrine by IBMX occurred in the raphe nuclei and that, based on these results and those of Barbaran and Aghhajanian (1980), both Alpha-1 and Beta-receptors activate postsynaptic neurons in the raphe nuclei (Reinhard et al., 1983). Studies of noradrenergic inputs onto serotonergic nerve terminals have reported that Alpha-2 receptors appear to be present on serotonergic nerve terminals in the hippocampus and occipital-parietal cortex. Specifically, in vitro brain slices (Gothert and Huth, 1980; Gothert et al., 1981; Frankhuyzen and Mulder, 1980)or synaptosomal preparations (Maura et al., 1982) from these brain regions were preincubated with r3H]-5HTP. The electrical or chemically induced release of this [3H]-5HTP was blocked by large doses of the Alpha-2 agonists clonidine or norepinephrine. The effects of clonidine or norepinephrine were themselves blocked by Alpha-2 antagonists. Frankhuyzen and Mulder (1980) postulated that norepinephrine terminals synapse onto Alpha-2 receptors located on serotonin terminals; the Alpha-2 receptors are therefore postsynaptic for the noradrenergic synapse and presynaptic for the serotonergic synapse. Serotonin synapses onto noradrenergic cells. These studies were conducted with brain tissue from the locus coeruleus nucleus, which contains an abundance of noradrenergic cell bodies. Global brain lesions of serotonin neurons were found to increase the activity of the rate-limiting enzyme for norepinephrine synthesis in the locus coeruleus (McRae-Deguerceet al., 1982).Thus serotonergic inputs onto noradrenergic cell bodies in this nucleus are thought to be inhibitory. Some parallel mechanisms may be series mechanisms. Although a number of antidepressant drugs appear to act in parallel on both noradrenergic and serotonergic brain systems, recent data suggest that some of these drugs may instead act through the two systems in a serial manner. Amitriptyline, on the one

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hand, has been reported to bind almost equally to noradrenergic and serotonergic reuptake sites, (1)decreasing both serotonin and norepinephrine metabolites in depressed patients; (2) affecting both noradrenergic and serotonergic behaviors in animals; and (3) reducing the density of Beta-adrenergic, serotonin-1, and serotonin-2 receptors. On the other hand, Gravel and de Montigny (1987) demonstrated that serotonin, iontophoresed onto hippocampal neurons, caused a decrease in cell firing. The chronic administration of amitriptyline exacerbated this inhibition of hippocampal firing, and the effect of amitriptyline was prevented by lesions of the noradrenergic system. Thus, at least in the hippocampus, the ability of amitriptyline to increase the sensitivity of postsynaptic serotonin receptors is dependent on intact noradrenergic inputs. A series mechanism whereby amitriptyline acts through noradrenergic neurons t o affect the serotonin system is postulated. Some series mechanisms may be single transmitter systems. As discussed under series mechanisms, a number of studies initially reported that the tricyclic, desipramine, and electroconvulsive therapy (ECT) appeared to require serotonergic neurons to downregulate Beta-adrenergic receptors. Specifically,lesions of serotonergic neurons with the neurotoxin, 5,7-dihydroxytryptamine, prevented chronic desipramine or ECT from decreasing the number of Beta-receptors in the cortex and hippocampus of rats (Brunello et al., 1982; Janowsky et al., 1982; Nimgaonkar et al., 1985; Sulser and Sanders-Bush, 1987). These data appeared to represent strong evidence in favor of a noradrenergic-serotonergic link hypothesis in the action of antidepressant drugs. More recently, evidence is accumulating that neither serotonin nor serotonergic neurons is required for desipramine or ECS-induced Beta-receptor down-regulation. By using nonlinear regression analysis on the receptor binding data, it has been shown that Betareceptors occur in both high- and low-affinity conformations (Manier et al., 1987). Furthermore, chronic desipramine (Gillespie et al., 1988, 1989; Manier et al., 1987) and ECS (Stockmeier and Kellar, 1988) decrease the number of Beta-receptors in high-affinity conformation only. These high-affinity receptors also interact with the CAMPsystem, which agrees with previous data that Beta-agonists increase CAMP(Nathanson, 1979). Conversely, 5,7-dihydroxytryptamine (5DHT)lesions of serotonergic neurons increase the number of Beta-receptors in the low-affinity conformation; high-affinity Beta-receptors were not affected by these lesions (Manier et al., 1987; Stockmeier and Kellar, 1988). Thus, the combinations of desipramine and 5DHT lesions, or ECT and 5DHT lesions, appeared to have no effect on Beta-receptors because the decrease in highaffinity receptors was masked by the increase in lowaffinity receptors.

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These recent data indicate that, in the cortex and agonists produced behavioral depressant effects in both hippocampus of rats, desipramine and ECT do not act animals and humans (e.g., Carlton, 1963)) and some via interactions between the Beta-noradrenergic and mood depressant effects of cholinomimetics had been serotonergic systems. Rather, these antidepressants noted (Janowsky et al., 1972). However, much more appear to act singularly through the noradrenergic information has accumulated in recent years on the system. However, these data do not preclude desi- possibility that pathological cholinergic mechanisms pramine or ECT-induced interactions between the two are involved in depressive disorders. Also, some importransmitter systems in other brain areas. tant insights have come from the development of an animal model of central cholinergic supersensitivity Conclusions and future directions hypothesized to underlie human affective disorders. Given the complexity of antidepressant drug action This evidence is summarized in the present section. and of the disease, depression, it is not surprising that Pharmacology of the cholinergic system multiple brain systems would underlie both the treatment and the disease. Furthermore, interactions beAcetylcholine is synthesized within neurons from tween different transmitter systems might be expected. acetyl coenzyme A (CoA) and choline. This reaction is This section has indicated that while some conflicting catalyzed by the enzyme choline acetyltransferase. Aldata exist, much evidence supports the interaction of a though not definite, acetyl CoA appears t o be synthevariety of antidepressant drugs with both the noradren- sized from glucose or citrate in the mitochondria ofbrain ergic and serotonergic systems. Behavioral, biochemi- neurons. Choline appears to be transported to the brain, cal, and electrophysiological data regarding specific in both the free and phospholipid forms, by the blood drugs and the interacting transmitter systems have (Cooper et al., 1986). The availability of choline is been reviewed. Two hypotheses of mechanisms of nor- normally the rate-limiting factor in the synthesis of adrenergic and serotonergic interaction have also been ACh. The availability of acetyl CoA may also regulate discussed, as well as recent data concerning changes in ACh synthesis under some circumstances (Tucek, 1984). these hypotheses. After ACh is synthesized and released from brain In the future, research on the interactions between noradrenergic and serotonergic systems in antidepres- neurons, it is hydrolyzed in the synaptic cleft by acetylsant drug action and in the mechanisms underlying cholinesterase. Free choline and acetic acid are formed, depression may take a more molecular direction. For and about one-half of the choline is transported back example, parallel mechanisms of antidepressant action into the presynaptic terminal, to be reused in ACh could involve serotonergic and noradrenergic receptors synthesis. ACh itself is not transported back into the on the same neurons. Changes in cell functioning could terminal in any appreciable quantity. Thus, cholinergic ultimately be caused by interactions between second function cannot be influenced by drugs that inhibit the messengers from the two types of receptors (Sulser and uptake of the transmitter, unlike the situation with Sanders-Bush, 1987). The two transmitter systems serotonin and the catecholamines. Cholinergic receptors are divided into two classes: might also interact at the level of gene expression muscarinic and nicotinic. Muscarinic receptors have (Sulser, 1989). Research on drug-induced changes in second messen- been further divided into two (some report as many as gers or gene expression might also resolve some of the four) subtypes. M1 receptors, in most areas, are posiconflicts of drug action resulting from different experi- tively coupled t o phosphoinositide hydrolysis, and M2 mental techniques. For example, imipramine has been receptors, in most areas, are negatively coupled to reported to decrease serotonin-1 receptor binding in the CAMPsynthesis. The identification and localization of hippocampus but to increase hippocampal neuron sen- nicotinic receptors is uncertain because of conflicting sitivities to serotonin. Fortunately, various research reports in the literature. These issues will be discussed groups have already begun to explore these possibili- further at a later point in this section. ties. Behavioral effects of cholinergic agonists in ACETYLCHOLINE (D.H. Overstreet and humans and animal models D. Janowsky) Physostigmine, a cholinesterase inhibitor or indirect The notion that acetylcholine (ACh)might be involved cholinergic agonist, has been found to induce depressive in depressive disorders was summarized in some of the symptoms in manics, as well as in a group of nonmanic early observations and comments of Janowsky and psychiatric patients, including depressives and schizocolleagues (1972). These workers proposed an adrener- affectives (Janowsky et al., 1974,1988). Physostigmine gic-cholinergic balance hypothesis, in which depression has also been found to induce depression in the majority was proposed to be due to a cholinergic predominance of a group of euthymic bipolar patients (Janowsky et al., and mania to the converse. At the time that the 1972 1973); Risch and colleagues (1981) reported that some paper was written, it was well known that cholinergic normals manifested depression after receiving physo-

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stigmine. Others have reported the induction of depression following the administration of direct cholinergic agonists, such as oxotremorine and arecoline, or the ACh precursors, choline, lecithin, and deanol (see Janowsky et al., 1988). There is also considerable evidence to indicate that the mood-depressant effects of a variety of cholinomimetic drugs are exaggerated in patients with affective disorders. While nearly all psychiatric patients who received physostigmine developed an inhibitory syndrome characterized by anergia, psychomotor retardation, and decreased thoughts, patients with depression or mania or a schizoaffective diagnosis became significantly more sad and depressed compared with schizophrenic subjects (Janowsky et al., 1974). In a more recent study, patients with affective disorder diagnoses were found to be significantly more reactive to the behavioral depressant and dysphoric effects of physostigmine than were normals and nonaffective disorder patients (Janowsky et al., 1980). Similar observations were made by Risch et al. (1981) after the administration of the direct agonist, arecoline. The Flinders Sensitive Line (FSL) of rats, selectively bred to be more sensitive to anticholinesterases (Overstreet et al., 19791, is also more sensitive to the behavioral depressant effects of physostigmine and direct cholinergic (muscarinic) agonists (Overstreet and Russell, 1982; Overstreet, 1986; Overstreet et al., 1988). Thus, this line of rats responds similarly to muscarinic agonists as do human depressives. This similarity in response to muscarinic agonists in FSL rats and human depressives extends to variables other than purely behavioral ones. For example, both groups exhibit exaggerated responses in the hypothalamo-pituitary-adrenal axis after being challenged with a muscarinic agonist (Overstreet et al., 1986a; Risch et al., 1981). The experimental subjects were administered the muscarinic agonist, arecoline, and greater elevations of the pituitary hormone, adrenocorticotropic hormone (ACTH), or the adrenal hormone, corticosterone, were observed in depressed humans (Rischet al., 1981)or FSL rats (Overstreet et al., 1986a), respectively. The FSL rats also have a shortened latency to REM sleep, as well as increased REM density (Shiromani et al., 1988). There are also well-known similar findings in human depressives (Shiromani et al., 1987). Depressed individuals also exhibit a greater reduction in REM latency following the administration of muscarinic agonists such as arecoline and RS-86 (Sitaram et al., 1982; Berger et al., 1989; Nurnberger et al., 1989). Thus, it is quite clear that cholinergic (muscarinic) agonists induce behavioral inhibition andlor depression-like symptoms in both animals and humans. In addition, however, the effects of these agents are greater in human depressives and in animals selectively bred for cholinergic supersensitivity on a range of behavioral and physiological indices.

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Biochemical measures in humans and animals Presynaptic cholinergic mechanisms A supersensitive response to physostigmine, as shown by the FSL rats and by human depressives (see Janowsky et al., 1988; Overstreet et al., 19881, could arise because of either pre- or postsynaptic mechanisms. However, the fact that both FSL rats and human depressives are also more sensitive to direct-acting muscarinic agonists suggests that postsynaptic mechanisms are involved. Until more sophisticated imaging techniques are evolved, it will be virtually impossible to obtain an index of presynaptic cholinergic function in the living human. The kinds of studies done on biopsied tissues from suspected Alzheimer patients are unlikely to be carried out on human depressives. Thus, all we know about the likely involvement of presynaptic cholinergic mechanisms in depression comes from the limited studies carried out on the presumably “depressed FSL rats. In one study, a tail vein injection of deuterium-labeled choline was followed by sacrifice by microwave fixation. Both endogenous and deuterium-labeled choline and ACh were determined by gas chromatography-mass spectrometry (GC-MS) for the cerebral cortex, hippocampus, midbrain, and striatum. The results showed that the FSL and control rats (the Flinders Resistant Line, FRL), had similar levels of choline and ACh in all regions of the brain except the cortex. In this region, the FSL rats had a higher level of labeled ACh than the FRL rats, suggesting a higher rate of synthesis (Overstreet et al., 1984). It therefore appears that there may be presynaptic cholinergic supersensitivity in the FSL rats with respect to the FRL rats, at least in the cerebral cortex. No follow-up studies have yet been done. The possibility of doing a comparable study in human depressives is very remote, so the status of the presynaptic cholinergic system in depression remains unknown.

Postsynaptic cholinergic mechanisms The increased sensitivity of the FSL rats to muscarinic agonists has been found to be associated with increased numbers of muscarinic acetylcholine receptors (mAChR) in the striatum and hippocampus (Overstreet et al., 1984). Interestingly, there were no changes in mAChR in the cortex of FSL rats, in which elevated synthesis of ACh was found; perhaps the increased synthesis of ACh counteracts the trend toward increased receptors in this region. In more recent studies, the increases in mAChR in the striatum and hippocampus have been confirmed, and small but significant increases in the hypothalamus and pons/midbrain have also been found (Pepe et al., 1988; Schiller et al., 1988, 1989). Preliminary studies suggest that both the M1 and M2 subtypes of the mAChR are elevated (Schiller et al., 1988, 1989). Thus, the increased sensitivity of FSL

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rats to muscarinic agonists could well be accounted for by the increased concentration of mAChR in many brain regions. Studies are underway to look at stimulation of phosphoinositide hydrolysis and inhibition of CAMP stimulation in order to assess second messenger function in the FSL rats. Studies on mAChR in human depressives have been punctuated by early promise and later disappointment. The early report of Nadi et al. (1984) that mAChR concentrations were higher in fibroblasts from patients with affective disorders has not been confirmed by other investigators, including the laboratory in which the original observations were made (Gershon et al., 1985; Kelsoe et al., 1985). More recent studies on blood cells appear to demonstrate reliable mAChR binding, but these studies have not yet been applied to individuals with depressive disorders (Moises eta]., 1988). There is still another problem with these mAChR studies. Given that the increased mAChR in the FSL rats is not uniformly observed even in all brain regions, it is not certain that the muscarinic supersensitivity postulated to be present in human depressives will be observed in peripheral tissues. In parallel with the fibroblast binding, an early study of brain mAChR binding in suicide victims reported an elevation of mAChR (Meyerson et al., 19821,but a later report did not find any differences (Kaufman et al., 1984).However, both studies used tissue from the cerebral cortex, and it is not clear whether this brain region has any relevance to the common symptoms of depressives, especially given a lack of increased mAChR binding in the cortex of FSL rats. Studies of the limbic regions of depressives, where muscarinic binding is increased in the FSL rats, are critically necessary before we can rule on the question of changes in brain mAChR in human depressives. Effects of antidepressants in humans and animals Most of the classical antidepressant drugs have welldocumented anticholinergic effects. It is common to view these latter effects as unwanted side effects. However, occasional commentaries have raised the possibility that the anticholinergic effects of ankidepressants may actually play a significant role in their therapeutic properties (e.g., Janowsky and Risch, 1984; MartinIverson et al., 1983). These papers cite anecdotal and experimental evidence that anticholinergics +ay exert antidepressant effects. Because of the common view on anticholinergic effects, very few investigators have studied the effects of antidepressants on cholinergic mechanisms. A sign of this lack of interest is the observation that a recent review on the effects of antidepressants on neurotransmitter receptors did not include a section on muscarinic receptors (Baker and Greenshaw, 1989). Other recent reviews have claimed that antidepressants do not affect muscarinic receptors, omitting citation of any of the papers that show that they do (Gleiter and Nutt, 1989; Newman and Lerer, 1989).

There is evidence from a number of independent laboratories that antidepressants with strong anticholinergic effects lead to an increase in mAChR concentrations in the brain (Goldman and Erickson, 1983; Rehavi et al., 1980) (Table 111). These increases are similar to, but not as widespread as, those seen after chronic treatment with the typical anticholinergics scopolamine and atropine (Goldman and Erickson, 1983). We have observed that rats that have been withdrawn from chronic treatment with amitriptyline or scopolamine exhibit a high degree of immobility in the forced swim test (Overstreet et al., 1986b). This “withdrawal depression” may be related to the withdrawal depressioddysphoridanxiety seen in some humans who discontinue their antidepressant medications (Dilsaver and Greden, 1984a,b). Thus, it is clear that many of the commonly used antidepressants have anticholinergic effects and that the chronic blockade of mAChR that accompanies treatment may lead to depressive-like symptoms during withdrawal (see Overstreet et al., 1988). Several antidepressants have been given to the FSL rats in an attempt to overcome their “depressive” tendencies. The degree of immobility in the forced swim test or in an open field chamber after exposure to a brief, mild footshock has been used to characterize the “depressive” tendencies of FSL rats and their control FRL counterparts. Both imipramine, a classical tricyclic antidepressant, and rolipram, a new-generation antidepressant that inhibits CAMPphosphodiesterase and has no obvious anticholinergic effects (Wachtel et al., 19881, were able to counteract the exaggerated shock-induced suppression of behavior in the FSL rats, whereas lithium did not (Overstreet and Double, 1987; Overstreet and Measday, 1985; Overstreet et al., 1989b). Surprisingly, rolipram led to a supersensitivity to cholinergic agonists, even though it had no acute anticholinergic effects (see Wachtel et al., 1988). Only a few studies have looked at muscarinically mediated second messenger function in animals chronically treated with antidepressants (see Newman and Lerer, 1989) (Table 111).They have not supported the hypothesis of a supersensitive CAMP response that could have been made from the model of Wachtel(1989). However, a recent study by Nomura et al. (1987) reported, some interesting results. These investigators found that amitriptyline and other tricyclic antidepressants were more efficient at blocking the effects of muscarinic agonists on M2 receptor-mediated inhibition of CAMP than on M1 receptor-mediated stimulation of phosphoinositide hydrolysis; therefore, these workers suggested that these compounds were selective for the M2 subtype (Nomura et al., 1987). By contrast, McKinney et al. (1988)were unable to replicate the results of Nomura et al. (1987), finding no evidence for the M2 muscarinic receptor selectivity of amitriptyline. Finally, the effects of lithium on cholinergic mechanisms need to be considered. Lithium is the most com-

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monly used prophylactic drug in the treatment of bipolar mood disorders, but its value in treating acute manic and/or depressive episodes is still disputed. There are conflicting data about the effects of lithium on cholinergic parameters. Several investigators have indicated that lithium treatment potentiates the effects of muscarinic agonists (Honchar et al., 1983; Jope et al., 1986, 1987). The effects of lithium on muscarinic receptors have been variously reported as producing no change (Overstreet and Double, 1987), or slight increases (Lerer, 1985) or as preventing the elevation normally induced by atropine (Levy et al., 1982).More recently, a conflict has arisen about the ability of lithium to influence muscarinically stimulated phosphoinositide (PI) hydroylsis: Kendall and Nahorski (1987) found a substantial decrease in PI hydrolysis in cortical tissues after chronic lithium treatment, whereas Casebolt and Jope (1989) did not. In any case, Casebolt and Jope reported more dramatic effects on noradrenergically mediated PI hydrolysis following chronic lithium treatment and suggested that this effect may be a more likely mechanism underlying the prophylactic effects of lithium than any change in cholinergic mechanisms. Even more recently, Avissar and Schreiber (1989) showed that lithium may block the ability of both carbachol, a muscarinic agonist, and isoproterenol, a Beta-adrenergic agonist, to induce increases in GTP-binding capacity. Since GTP-binding capacity, reflecting G-protein function, is necessary for second messenger function to occur, these investigators believe that their findings are compatible with the antimanic and antidepressant effects of lithium (see Baraban et al., 1989).

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and physiological phenomena that are known to change with depression, First, however, a brief description of the new developments in molecular information about muscarinic and adrenergic receptors will be provided to serve as a background for the functional studies to be described later. Molecular data It is important to recognize that the noradrenergic and muscarinic receptors are heterogeneous. Pharmacologically,there are at least four types of noradrenergic receptors and two types of muscarinic receptors, although recent studies suggest that there may be more (Norman et al., 1989; Venter et al., 1988, 1989). These are the Beta (Bl, B2),Alpha (A1andA2)for norepinephrine and M1 and M2 for ACh. The Beta receptors are coupled positively to CAMP through G proteins, while the M2 receptors are coupled negatively to CAMP through a different group of G proteins. So for CAMP,the cholinergic and noradrenergic systems are opposing systems. On the other hand, both A1 and M l receptors are linked positively to the stimulation of PI hydrolysis; i.e., they are parallel systems. It is also important to reocgnize that these receptors may be localized either on presynaptic terminals or on postsynaptic processes, or both. Some of the pharmacological studies considered in the following sections have assumed that a particular drug was acting preferentially on presynaptic terminals. Most recent data on noradrenergic and muscarinic receptors have been accumulated from molecular genetic studies. By cloning the receptors, it has been possible to obtain a clearer picture of their structure. Such studies have demonstrated that there appear to be at least four subtypes of muscarinic receptors (Bonner, 1989) and that there is considerable structural overlap (homology)between the muscarinic and adrenergic receptors (Venter et al., 1988, 1989). Studies in a wide range of animals suggest that these receptors are quite old evolutionarily and that they may have evolved from a common ancestor gene (Venter et al., 1988).How could such similar proteins have such different functions? The answeds) to this question is (are) still being explored. However, a favored suggestion is that the receptors may be coupled to different G proteins (Venter et al., 1989).

Cholinergickatecholaminergicinteractions The classical pharmacological studies of the autonomic nervous system have provided the basis for the long established concept that the noradrenergic system mediates behavioral arousal and the cholinergic system mediates behavioral inhibition. Carlton (1963) extended these concepts to behaviors thought to be mediated by the brain; Janowsky et al. (1972) applied the concept to the regulation of mood. As further experimental studies have been carried out, it has become clear that this simple model can only be maintained in very general terms. First, it has become apparent that the autonomic ganglia contain a large number of neurotransmitter and neuromodulator substances in addition Appetitive behaviors Grossman (1962a,b) was one of the first to suggest to norepinephrine and acetylcholine (Furness et al., 1989).Second, some of the behavioral actions previously that drinking and eating may be neurochemically coded attributed to norepinephrine are probably more likely by ACh and NE, respectively. Other workers during the mediated by dopamine (Roberts et al., 1975; Bloom et 1960s generally replicated these results. Some investial., 1989). Third, the nature of the interaction between gators even reported that it was possible to elicit drinkcholinergic and noradrenergic systems may depend on ing in a hungry, nonthirsty rat by applying carbachol, a the specific brain region in which the interaction is cholinergic agonist, into the lateral hypothalamus. occurring, with both parallel or facilitatory, and oppos- When investigators examined the possible reciprocal ing or inhibitory arrangements being possible. This interaction of NE and ACh in eating, a controversy section considers cholinergic-adrenergic and cholin- developed. Using central administration of the transergic-dopaminergic interactions in several behavioral mitters and analogs, Singer and Kelly (19721, reported

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that stimulation of the cholinergic system inhibited eating, while stimulation of the adrenergic system inhibited drinking. By contrast, Stark et al. (1971) reported that physostigmine lowered the threshold for the elicitation of eating by electrical stimulation of the hypothalamus. Apparently this discrepancy has never been resolved. Instead, the notion of cholinergically coded drinking and noradrenergically coded eating tended to go out of vogue when it became evident that (1) ACh did not mediate drinking in other species of mammals; (2)the dipsogenic effects of angiotensin in numerous species was detected; and (3) compounds affecting other neurotransmitter systems could influence either drinking or feeding, or both. It is not our purpose here to provide an up-to-date review of the neurochemical systems underlying appetite. Rather, it is important to recognize that the historical coding concept is no longer tenable. A balance model, in which ACh and NE are in balance with other neurotransmitters, is still a useful model, however. One implication of such a model is that a selective change in one of the systems involved in the balance could result in a change in the parameter being measure‘d. Thus, either a selective decrease in NE or a selective increase in ACh (e.g., Singer and Kelly, 1972) might lead to decreases in eating. Since a decrease in appetite is commonly found in human depressives, one could speculate that either cholinergic overactivity or noradrenergic underactivity might underlie this symptom.

Arousal Classically, noradrenergic stimulation leads to behavioral arousal, just as physiological arousal is mediated by the noradrenergic sympathetic system (Carlton, 1963). By contrast, cholinergic stimulation leads to behavioral depression or inhibition, just as physiological conservation is mediated by the cholinergic parasympathetic system (Carlton, 1963). These views developed from the observations that, in general, cholinesterase inhibitors and cholinergic agonists produced behavioral depression, while cholinergic blockers and amphetamine, thought to promote the release of NE, stimulated activity (see Janowsky et al., 1972). These studies were reinforced by other studies that demonstrated that cholinergic stimulation could counteract the behavioral excitation induced by adrenergic stimulation (Fibiger et al., 1970; Janowsky et al., 1973). More recent studies have reinforced the view that ACh is generally a behavioral “inhibitory” transmitter (Janowsky et al., 1988; Overstreet et al., 1988),but that this inhibition may be brain location specific (see Flick and Geyer, 1982). However, there has been a shift in opinion about the role of NE. Several studies have suggested that the stimulatory effects of amphetamine on motor activity can only be modified by destroying dopaminergic neurons (Creese and Iversen, 1975; Roberts et al., 1975). Thus, it may be more appropriate to

talk about a dopaminergic-cholinergic interaction in the control of motor activity. Anatomical studies of the striatum reinforce this notion; the nigrostriatal dopamine neurons synapse on cholinergic neurons or their terminals (Lehmann and Langer, 1983). Another problem with noradrenergic mechanisms being involved in behavioral arousal is the observation that both Alpha- and Beta-adrenergic agonists reduce locomotor activity. Some have argued that the effects of clonidine, an Alpha-2 agonist, are due to its stimulation of presynaptic receptors, leading to the reduction in NE turnover (e.g., Drew et al., 1979). However, more recent studies suggest that the behavioral depressant effects of clonidine are due to interactions with postsynaptic receptors (Spyraki and Fibiger, 1982). No presynaptic mechanism has been invoked to explain the effects of Beta-agonists. These psychopharmacological data are at odds with earlier studies which showed that intraventricularly applied NE led to increases in activity (Segal and Mandell, 1970). It is clear that generalized cholinergic stimulation leads to behavioral depression and that dopaminergic stimulation leads to behavioral excitation. The specific role of NE in behavioral arousal still needs to be resolved. Since many human depressives suffer from psychomotor retardation, one could expect there to be an underactive dopaminergic system or an overactive cholinergic system or both in depression. It is interesting to note that the FSL rats, which tend to be more immobile after mild stressors than FRL rats, have both of the above neurotransmitter alterations (Overstreet et al., 1988).Thus, they are subsensitive to the stereotypyinducing effects of the dopamine agonist, apomorphine, as well as supersensitive to the behavioral depressant effects of the cholinergic agonist, oxotremorine (Crocker and Overstreet, 1984). Anhedonia Anhedonia, the inability to experience pleasure, is a very common symptom in individuals with depressive disorders (Whybrow et al., 1984). There is considerable debate about the mechanisms underlying this behavioral state, with most investigators proposing that a dopamine deficiency, rather than a norepinephrine deficiency, might be involved (German and Bowden, 1974; Sachar, 1985; Wise, 1978; Whybrow et al., 1984). However, virtually all of the recent reviews on this topic have overlooked the older literature demonstrating that cholinergic agonists could reduce the rate of bar pressing for rewarding electrical brain stimulation (Domino and Olds, 1968; Stark et al., 1971; Newman, 1972). A prominent exception is the recent review by Tandon and Greden (1989) suggesting that the negative symptoms of schizophrenia, including anhedonia, might be due in part to an overactive cholinergic system. Thus, rather than reward and its absence being controlled solely by a single neurotransmitter, it is more

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likely that a balance among neurotransmitters is involved. Inhibition of reward can be brought about either by stimulation of the cholinergic system or by blockade of the dopaminergic system. Support for cholinergic involvement in anhedonia comes from observations of the cholinergically supersensitive FSL rats. These rats took longer to acquire an operant response for water reward and responded at much lower (50%)rates on the final fixed-ratio task (Overstreet and Russell, 1982; Russell et al., 1982). Although these results may be a consequence of locomotor activity differences, they may also be accounted for by the hypothesis that the FSL rats obtain less reward from water. Since anhedonia is common in depressive disorders and can occur as a result of either cholinergic overactivity or dopaminergic underactivity, it is not possible to make any conclusive statement about cause and effect. Clearly, either one or both systems could be involved. However, it should be emphasized that most investigators have neglected the potential role of the cholinergic system. Sleep There have been well-documented changes in sleep in human depressives, including a shortened latency to REM sleep and increased REM density, phenomena that also occur after muscarinic agonist administration (Shiromani et al., 1987). The FSL rats, selectively bred for increased cholinergic function, also show shortened REM latency and increased REM density (Shiromani et al., 1988).These observations led to the hypothesis that the REM sleep abnormalities in human depressives may be the consequence of a cholinergic supersensitivity. However, consideration of the literature on sleep mechanisms in animals suggests that the data may be consistent with noradrenergic subsensitivity as well. Hobson et al. (1975)were among the first to observe that pontine cholinergic neurons fired in a reciprocal pattern t o that of locus coeruleus noradrenergic neurons. The rhythmical firing of these two nuclei was postulated by Hobson et al. (1975) to underlie the REM sleep cycle. Thus, one couId speculate that adrenergic underactivity could also lead to reduced REM latency on the basis of this model. Other observations in human depressives have provided support for the cholinergic supersensitivity model (Nurnberger et al., 1989; Sitaram et al., 1982). These studies have routinely shown that patients with the diagnosis of endogenous depression exhibited a significantly greater shortening of REM sleep latency than did control subjects or patients with other diagnoses. The question of whether this is a state or trait phenomenon has not been resolved (cf. Berger et al., 1989; Sitaram et al., 1987). However, there do not appear to be any studies that have attempted to test the noradrenergic subsensitivity model. Thus, this model cannot be re-

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jected purely on the basis of the large support for the cholinergic model. Quite clearly, both may occur. Neuroendocrine measures The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in depression. It is well known, for example, that many depressed patients have elevated levels of cortisol and others show an early escape from cortisol suppression by the synthetic glucocorticoid, dexamethasone (Janowsky et al., 1988). Whether these abnormalities are due to some intrinsic changes in the HPA axis or to dysfunctions in neurotransmitter systems that impinge on hypothalamic neurons containing corticotropin-releasing factor (CRF) is under debate. Recent investigators have reported elevations of CRF in the cerebrospinal fluid (CSF)in human depressives and a blunted ACTH response to administered CRF (Nemeroff et al., 1988). These data are consistent with the hypothesis that the pituitary ACTH cells have become subsensitive as a result of excessive release of CRF, brought about by abnormalities in brain pathways impinging on the CRF neurons. Various studies are consistent in reporting that cholinergic stimulation leads to an activation of the HPA axis (see Janowsky and Risch, 1984; Janowsky et al., 1988; Overstreet et al., 1988). Both human depressives and the FSL rats exhibit supersensitive hormonal responses to cholinergic stimulation (Overstreet et al., 1986a; Risch et al., 1981). Other studies have provided controversial data on the role of the noradrenergic system in control of the HPA axis. Some reviewers have indicated that most evidence suggests that the noradrenergic system exerts inhibitory control over the axis (Ganong, 1980; Arnold and Martin, 1989). Others have interpreted the dexamethasone nonsuppression data as consistent with the hypothesis of noradrenergic subsensitivity (e.g., Sachar, 1985). There do not appear to be any direct tests of noradrenergic subsensitivity, except for the clonidine provocation studies, in which depressives and normals are given various doses of clonidine and blood is withdrawn a t particular time intervals for assessment of cortisol or other hormones. While these studies are in general agreement with the noradrenergic subsensitivity model (i.e., a blunted response in the depressives), there are difficulties in interpretation. The data suggest that there is a reduced sensitivity of Alpha-:! adrenoceptors in depressives; such an outcome could be the consequence of excessive presynaptic release of NE. However, the classical catecholamine hypothesis suggested that there was a deficiency of NE release or turnover. More study is necessary. A recent article by Leibowitz et al. (1989)has demonstrated conclusively that the direct administration of norepinephrine into the paraventricular nucleus of the hypothalamus leads to an elevation of serum corticosterone. These investigators also referred to other

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evidence consistent with both excitatory control of norepinephrine and serotonin over hypothalamic CRF neurons. These recent findings, if replicated by other laboratories, offer a different perspective on the basis of the neuroendocrine abnormalities in depressive disorders: they are consistent with the cholinergic supersensitivity model but not with the noradrenergic or serotonergic deficiency models.

Peter Shiromani and colleagues at U.C. San Diego will be investigating circadian rhythms. Preliminary evidence suggests that the temperature rhythms of the FSL rats are phase-advanced relative to the control, FRL rats. Thus, the cholinergic supersensitivity and circadian rhythm models of depression may be overlapping. Dr. John Nurnberger, Jr., and colleagues a t the Indiana University Institute of Psychiatric Research, are also involved in joint animal and human studies that might interweave. They have been looking at two inbred mouse strains that differ in their sensitivity to cholinergic agonists. By looking at recombinant inbreds as well, they may be able to detect single gene effects (Nurnberger et al., 1988). Some work suggests that the muscarinic response is influenced by both dominant and additive genetic factors. One of the cloned muscarinic receptors (Bonner, 1989)may be located on chromosome 11.So may be a major gene affecting bipolar illness in the Amish (Egeland, 1988). Consequently, another major thrust of Dr. Nurnberger’s group is the collection of pedigrees containing individuals with bipolar illness and conducting molecular genetic studies in an attempt to replicate the findings in the Amish. A problem that could affect the above attempt to replicate the Amish study is the contamination of the bipolar pedigrees with alcoholics. In fact, depression and alcoholism overlap to a significant extent in most studies. Recently, we proposed that the cholinergic challenge might be used to help differentiate primary alcoholics from primary depressives (Overstreet et al., 1989). While depressives appear supersensitive to cholinergic agonists relative to controls, alcoholics are subsensitive (Janowsky, 1989). Therefore, the difference between a primary depressive and a primary alcoholic should be extremely large, so that each individual could be tested independently. A large family study of alcoholism at the University of North Carolina may incorporate this challenge approach. Because depressive disorders are heterogeneous disorders, it is unlikely that any single neurotransmitter abnormality can provide a complete explanation of the behavioral symptoms. Unfortunately, most investigators have chosen the unitary approach. Recently, we have begun to explore the status of other neurotransmitter systems in the FSL rats, selectively bred to have cholinergic supersensitivity, and distinct changes have been seen (Overstreet et al., 1988).A similar approach is needed for the human studies; challenging with a specific drug that affects the cholinergic system tells us little if we know nothing about the status of other neurotransmitter systems in the same patients.

Conclusions and future directions Both depressed humans and FSL rats-a genetic animal model of depression-are more sensitive to the behavioral and physiological effects of cholinergic agonists than are their normal human or FRL rat counterparts. In FSL rats, these increased responses are accompanied by elevated muscarinic receptors, while the human studies to date have been inconclusive. There are occasional hints in both the human and animal data that antidepressant drugs may be operating through cholinergic mechanisms; however, the large majority of investigators have neglected such an association. Virtually every behavioral or biochemical parameter reviewed in this section was regulated, to some degree, by opposing cholinergic and catecholaminergic systems; if the cholinergic system stimulated the parameter, then the catecholamine system inhibited it. Because these parameters are often abnormal in human depressives and because the cholinergic-catecholaminergic interactions are opposing, it is frequently impossible to obtain conclusive evidence supporting the unitary catecholamine or cholinergic hypotheses. It is even possible that both neurotransmitter abnormalities may be present in some human depressives. Future directions for acetylcholine-depression research include studies being pursued by our colleagues as well as topics that are not yet being examined. Gaps in our knowledge include a lack of correlation of cholinergic challenge data with diagnostic subgroups of affective disorders. For example, do bipolar depressives have the trait of cholinergic supersensitivity, while unipolar depressives have only the state? This is also true of measurement of muscarinic acetylcholine receptors (mAChR) in limbic and other brain regions thought to participate in depression from suicides. Dr. Chris Gillin and colleagues a t the University of California (U.C.), San Diego, have begun to examine the question of mAChR subtypes that may be involved in effects on normal and depressed humans. For example, does the selective M1 agonist, biperiden, have an antidepressant effect in controlled trials? There are reasonable anecdotal and open-trial data to suggest that it might. In a parallel study, these workers plan to examine the effects of biperiden on sleep parameters in DOPAMINE, GABA, AND PEPTIDES normals. Since REM sleep generation is influenced ( S . Caldecott-Hazard) exclusively by M2 receptors (Velazquez-Moctezumaet Biochemical theories of mood disorders usually stress al., 1989),it is anticipated that biperiden will not influence REM sleep at low doses. In another study, in which noradrenergic, serotonergic, and, to a lesser extent, the selectively bred FSL and FRL rats will be used, cholinergic mechanisms. However, other neurochemi-

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cals such as dopamine, gamma-aminobutyric acid (GABA), and peptides have also been implicated in the mechanisms underlying depressive symptomology and antidepressant treatments. This section reviews some of these recent data.

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may be classified as dopamine-2 (D-2) receptors. This classification also includes postsynaptic receptors that use cyclic adenosine monophosphate (CAMP)as a secondary messenger (Roth et al., 1987). Postsynaptic dopamine receptors are subdivided into dopamine-1 (D-1) and dopamine-2 (D-2) types. Agonist Dopamine stimulation of D-1 receptors leads to an increase in the Pharmacology of the dopaminergic system secondary messenger (CAMP);conversely, agonist stimSince norepinephrine is synthesized from dopamine, ulation of D-2 receptors leads to decreased CAMPformathe pathways for the formation ofthese transmitters are tion (Creese, 1987). There are four major dopamine systems in the brain; identical, except for the final step. The primary synthein addition to their anatomical locations, they may be sis pathway begins with the amino acid tyrosine in the distinguished by their complements of receptor types nerve terminal. Tyrosine is converted to 3,4-dihydroxyand by their feedback systems. For example, the tuberophenylalanine (DOPA) by the enzyme tyrosine hydroxinfundibular system (with cell bodies in the hypothalaylase; DOPA is then transformed to dopamine by aromus and terminals in the median emminence) is matic amino acid decarboxylase (DOPA decarboxylase). Dopaminergic nerve terminals do not contain the en- thought to have only D-2 postsynaptic receptors, and zyme dopamine Beta-hydroxylase, which would convert regulatory feedback occurs via its released hormones (Rubin, 1987). Other dopamine systems, such as the dopamine to norepinephrine. nigrostriatal (cell bodies in the substantia nigra and The secondary pathway for dopamine formation also terminals in the caudate nucleus and globus pallidus) or begins with tyrosine. This amino acid is converted to mesolimbic (cell bodies in the ventral tegmental area tyramine by aromatic amino acid decarboxylase; and terminals in the accumbens, septum, amygdala, tyramine is then transformed into dopamine by catepiriform cortex, and olfactory tubercle), have neurochol-forming enzyme (Cooper et al., 1986). Unfortutransmitter-mediated, reciprocal-neuron feedback cirnately, the role and importance of this secondary pathcuits; they also have D-1, D-2, and all types of autoreway are not well understood. ceptors. By contrast, the prefrontal and cingulate Dopamine is inactivated by two enzyme pathways. branches of the mesocortical dopamine systems (cell When this transmitter is released from a nerve terminal, much of it is subsequently taken up into the same bodies in the ventral tegmental area and terminals in the medial prefrontal, cingulate, and entorhinal cortipresynaptic terminal (Roth et al., 1987). Intraneuronces) are devoid of both somatodendritic and synthesis ally, it is converted into an aldehyde by intraneuronal MA0 and then into 3,4-dihydroxyphenyl acetic acid modulating autoreceptors (Cooper et al., 1986). (DOPAC)by aldehyde dehydrogenase. Dopamine is also converted, probably at an extraneuronal site, into 3- Biochemical measures in humans and methoxytyramine (MTA)by COMT. MTA is acted on by animal models Although variability exists in the data, a number of MA0 to form an aldehyde that is transformed into homovanillic acid (HVA) by aldehyde dehydrogenase. studies suggest that dopaminergic activity in the brain While DOPAC is the predominate metabolite in the is reduced in some subgroups of depressed patients and brain of rats, HVA predominates in primates. Both is increased in manic patients (Table 11).Decreased CSF metabolites can be measured in the cerebrospinal fluid levels of the dopamine metabolite HVA have been reported in depressed patients. The studies that produced (CSF). Dopamine receptors are divided into two categories: these results used experimental groups, in which paautoreceptors (receptors on the soma, dendrites, or tients were given drug washout periods prior to testing, presynaptic terminals of the dopaminergic neuron; and control groups that were age and sex matched to the these receptors respond t o their own transmitter); and experimental groups (Asberg et al., 1984; Berger et al., postsynaptic receptors (receptors on a postsynaptic neu- 1980; Goodwin et al., 1973; Jimerson and Berrettini, ron, which respond to the dopamine released by the 1985; Koslow et al., 1983; Papeschi and McClure, 1971). presynaptic neuron). Autoreceptors are further divided Although the sample size was small, both unipolar and into those that modulate the rate of tyrosine hydroxy- bipolar patients were reported to have similar, reduced lase (hence dopamine synthesis), those that modulate levels of HVA (Jimerson and Berrettini, 1985;Asberg et the release of transmitter from the terminal, and soma- al., 1984).When depressed patients were not given drug todendritic receptors that modulate impulse flow. It is washout periods or not compared with matched conthought that the three autoreceptor types may act via trols, HVA levels were reported to be either increased or different second messenger systems (Roth et al., 1987). not changed, compared with controls (Gerner et al., For example, a methyltransferase-dependent signal 1984; Subrahmanyam, 1975).Interestingly, CSF levels transduction step may be involved in the action of of HVA have been reported to be elevated in depressed release-modulating autoreceptors (Roth et al., 1987). patients that also showed psychotiddelusional sympNerve terminal, synthesis modulating autoreceptors toms (Aberg-Wistedt et al., 1985; Sweeney et al., 1978).

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Other methods for assessing dopaminergic activity in the brain include the measurement of plasma prolactin or growth hormone levels under baseline conditions or following pharmacological challenges. Dopamine-containing cells are located in the arcuate and periventricular nuclei of the hypothalamus, and the terminals of these cells release dopamine into the median eminance (tuberoinfundibular system). Dopamine is then transported via the hypothalamic-hypophyseal portal circulation to cells that secrete either prolactin or growth hormone in the anterior pituitary. Dopamine is known to inhibit the secretion of prolactin and stimulate the secretion of growth hormone. Thus, alterations in the hypothalamic-pituitary dopamine systems attributable to depression might be expected to affect plasma levels of prolactin or growth hormone. Unfortunately, studies of basal plasma levels of these hormones have reported no consistent differences in depressed patients as compared with controls. Likewise, responses of these hormones following the administration of dopamine agonists, such as apomorphine, were not abnormal in depressed patients (Jimerson, 1987). However, since the various brain dopamine systems differ in both function and kinds of receptors, a lack of change in the tuberoinfundibular system is not indicative of possible changes in the other systems during depression. Dopamine agonists, such as piribedil and bromocriptine, have been reported in some studies to have measurable antidepressant effects (Nordin et al., 1981; Post et al., 1978; Waehrens and Gerlach, 1981). However, others have reported dysphoria following initial improvement with piribedil (Shopsin and Gershon, 1978). Animal studies indicated that a selective D-1 receptor agonist, SKI? 38393, acted as an antidepressant (Serra et al., 1988)in both the behavioral despair (Porsolt et al., 1978)and learned helplessness (Seligman and Beagley, 1975)models of depression. Finally, stress has been proposed as a factor in the precipitation of depression, particularly nonbipolar disorder (Paykel, 19831, and various studies using animal models support a role for dopamine in this condition. Interestingly, the type and intensity of stress may determine whether dopaminergic activity is increased or decreased, and in what brain areas this change occurs. For example, female rats forced to run in revolving cages for prolonged periods showed decreased fluorescence of dopamine cell bodies and terminals in the tuberoinfundibular system as compared to controls (Hatotani et al., 1979).Repeated daily footshock stress, of a mild intensity, reduced dopamine metabolism in the ventral tegmental area (VTA),and increased dopamine metabolism in the prefrontal cortex (Kalivas and Duffy, 1989). However, in contrast to repeated stress, acute mild stress increased DOPAC in the VTA (Deutch et al., 1985).A single episode of mild footshock stress (~0.4 mA) also increased DOPAC levels in the prefrontal cortex (Kalivas and Duffy, 1989; Deutch et al., 1985; Dunn, 1988).More intense, acute stress (>0.4mA) increased

dopamine metabolism in the mesolimbic and nigrostriatal terminal fields, as well as in the prefrontal cortex (Dunn, 1988; Speciale et al., 1986). Effects of antidepressants on neurochemistry Many established antidepressant treatments, which were previously thought to affect noradrenergic and serotonergic systems, are now also reported to alter dopamine systems (Table 111). For example, chronic administration of tricyclic antidepressants prevents a decrease in rat brain DOPAC induced by the dopamine agonist, apomorphine (Serra et al., 1979). This effect may be due to a subsensitivity of inhibitory somatodendritic autoreceptors that is reported to be induced by the repeated administration of tricyclic antidepressants (Chiodo and Antelman, 1980a,b). However, other investigators have not been able to replicate the decreases in autoreceptor sensitivity by tricyclic antidepressants (Welch et al., 1982; MacNeil and Gower, 1982). Chronic tricyclic administration has also been reported to reduce the number of D-1, postsynaptic, receptors in the rat limbic system and striatum (De Montis et al., 1989; Klimek and Nielsen, 1987).By contrast, tricyclic antidepressants produced no changes in [3Hlspiperone binding, which labels D-2 receptors (Klimek and Nielsen, 1987; Peroutka and Snyder, 1980). Behavioral tests in rats have also supported a dopamine-enhancing effect of tricyclic antidepressants. Intracranial self stimulation from the dopaminergic cells of the VTA (Fibiger and Phillips, 1981), apomorphineinduced aggression (Maj et al., 1979), and dopamineinduced locomotion (Plaznik and Kostowski, 1987)were all enhanced following administration of repeated tricyclic antidepressants. Unfortunately, while tricyclic antidepressants reduced depressive symptoms in patients, these drugs did not alter CSF (Papeschi and McClure, 1971) or urinary levels (Linnoila et al., 1983) of the dopamine metabolite HVA. Like tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and lithium have been reported to alter dopamine systems in rat brain. Repeated administration of MAOIs causes the subsensitivity of inhibitory, dopamine autoreceptors, thereby increasing the release of dopamine from nerve terminals (Antelman et al., 1982). Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity produced by the repeated administration of haloperidol (Pert et al., 1978). In addition to antidepressant drugs, electroconvulsive shock therapy (ECT) may also act, in part, via dopaminergic systems. ECT causes both a subsensitivity of dopamine autoreceptors (Chiodo and Antelman, 1980c)and a reduction of D-1 receptors (De Montis et al., 1990; Klimek and Nielsen, 1987) in rat brains. Dopamine-induced locomotion and active swimming in the Porsolt test (unlike depression-induced immobility) are both enhanced after ECT (Plaznik and Kostowski,

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1987). Also, in depressed patients, the decrease in plasma prolactin levels caused by apomorphine injections is enhanced after ECT (Balldin et al., 1982). Finally, new antidepressant drugs have been developed that are thought to act relatively specifically via the blockade of dopamine uptake. These drugs include nomifensine, buproprion, and minaprine.

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al., 1982). However, other studies did not find significant differences in CSF GABA content between depressed and control individuals (Post et al., 1980). Furthermore, reductions of CSF GABA levels are not unique to depressed patients; schizophrenics (van Kammen et al., 1980), epileptics (Wood et al., 19801, and patients with Huntington’s chorea (Glaesar et al., 1975) are all reported to have decreased levels of this amino acid. However, data that further support a GABA deficiency in depressed patients include a report of decreased GAD levels in the brain (especially frontal cortex and striatum) in depression (Perry et al., 1977). Also, the binding affinities (Kd) of GABAB receptors were decreased in antidepressant-free suicide victims as compared with suicide victims who had received such drugs (Cross et al., 1988). Animal models of depressed behavior also provide support for the hypothesis that GABA dysfunction is related to the pathophysiology of mood disorders. In the learned helplessness model in rats, the release of GABA from hippocampal slices decreased in parallel with the development of abnormal behaviors (Petty, 1986). The number of GABAB receptors in the frontal cortex was also decreased in this model, as well as in the olfactory bulbectomy model (Lloydet al., 1990)and in a footshockinduced stress model (Biggioet al., 1981).GABABreceptors were also decreased in the striatum, but not in the cerebellum. While a decrease in receptor numbers is the opposite of what would be expected if GABA levels were decreased in depression (e.g., compensatory upregulation of receptors), the decrease in receptors in the helplessness model was in a different location (frontal cortex) from the decrease in GABA release (hippocampus). However, it is not clear how one should interpret decreased GABA receptor numbers in the frontal cortex of depressed rats vis-a-vis decreased GAD activity (GABA synthesis) in the frontal cortex of depressed patients. The decrease in GAD in the frontal cortex of depressed patients was not replicated by similar studies in suicide victims (Cheetham et al., 1988b).

Pharmacology of the GABAergic system The amino acid, gamma-aminobutyric acid (GABA), is primarily synthesized from glutamic acid by the enzyme glutamic acid decarboxylase (GAD). This reaction is thought to take place in the axoplasm of nerve terminals. After release from the neuron, GABA is taken up into its own nerve terminals or into glial cells by high-affinity uptake systems (Fonnum, 1987).GABA is inactivated to succinic semialdehyde by the enzyme GABA-transaminase (GABA-T), then further metabolized to succinic acid by succinic semialdehyde dehydrogenase. GABA receptors include a GABAAtype, located a t the “classical” GABA synapse, that regulates chloride fluxes; and a GABAB type, not associated with chloride fluxes, but whose activation causes a decrease in calcium conductance and an increase in potassium conductance (Lloyd and Morselli, 1987). In addition, some reports have suggested that presynaptic autoreceptors may regulate the release of GABA from nerve terminals (Johnston and Mitchell, 1971). GABAAreceptors are also part of a GABA benzodiazepine-chloride iontophore macromolecular complex that includes recognition sites for GABA and its agonists, benzodiazepines and benzodiazepine-displacing agents, barbiturates and picrotoxin, and modulatory proteins such as GABA-modulins and diazepambinding inhibitor (Lloyd and Morselli, 1987). While some of these substances are capable of affecting each other at the macromolecular complex, they are not necessarily involved in mediating the same behaviors. For example, although benzodiazepines can enhance the binding of GABA at GABAAreceptors, clinical re- Effects of antidepressants on neurochemistry sults and many animal studies do not support a major As with the dopamine system of the brain, the GABA anxiolytic role for GABAergic agonists (Lloyd and Mor- system is affected by antidepressant treatments which selli, 1987). were previously thought to act via noradrenergic or serotonergic mechanisms only (Table 111).Some tricyBiochemical measures in humans and clic antidepressants have been found to block the upanimal models take of GABA (Lloyd et al., 1987). However, this effect A number of studies have found that plasma levels of was not of great magnitude. A more consistent finding is GABA are significantly lower in patients with depres- that tricyclic antidepressants, such as amitriptyline, sive disorders (Coffmann and Petty, 1986; Petty and desipramine, or imipramine; MAOIs, such as pargyline; Schlesser, 1981), including euthymic bipolar patients serotonin uptake inhibitors, such as fluoxetine and (Berrettini and Post, 19841, as compared with controls zimelidine; and electroconvulsive shock therapy have (Table 11).Likewise, several reports indicate that CSF been reported to increase the number of GABABreceplevels of GABA are lower in depressed patients than in tors in the frontal cortex of rats (Lloyd et al., 1987; controls (Gerner et al., 1984; Gold et al., 1980; Kasa et Szekely et al., 1987) or mice (Suzdak and Gianutsos,

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1986).Other researchers have reported that antidepressants do not induce changes in GABA, receptors (Cross and Horton, 1987). Perhaps an explanation for this receptor discrepancy lies in reports that desipramine increased GABA, numbers only in rats, given olfactory bulbectomies, whose passive avoidance deficits were corrected by the antidepressant. Rats that did not respond behaviorally to the drug also failed to show up-regulation of GABAB receptors (Joly et al., 1987; Lloyd et al., 1999). Recent studies indicated that many GABAergic mimetic drugs may have antidepressant activity in humans and animal models. Progabide and fengabine (each agonists at both GABAA and GABAB receptors) were reported to be as effective as tricyclic antidepressants in alleviating depressive symptoms, with fewer adverse side effects (Perris et al., 1986; Morselli et al., 1980; Musch, 1986). Valproate (also active at both GABA receptors) is effective in mania and in “mixed affective disorders’’(Lloydet al., 1989).It is notable that GABA agonists that are relatively specific for either the A (e.g., THIP) or B (e.g., baclofen) type of receptors are not very effective as antidepressants in humans (Lloyd et al., 1989). Selective GABA mimetics have been reported t o produce antidepressant effects in some animal models of depressed behavior. For example, baclofen (GABAB agonist) decreased muricidal and elevated open field behaviors in olfactory bulbectomized rats (Delina-Stula and Vassout, 1978; Leonard, 1984).Likewise, muscimol (predominantly a GABAA receptor agonist with weak GABAB activity) partially reversed the passive avoidance deficit in rats with olfactory bulbectomies (Lloyd et al., 1983), reduced immobility in the Porsolt swimming test (Aley and Kulkarni, 1989; Borsini et al., 1986; Poncelet et al., 19871, and reversed escape failures in the learned helplessness paradigm (Poncelet et al., 1987). THIP (a selective GABAA agonist) also reduced immobility in the Porsolt test (Borsini et al., 1986). However, some researchers believe that the more potent antidepressant effects in animals are produced by mixed GABAA+B agonists. Progabide and fengabine have been found to correct the passive avoidance deficit in olfactory bulbectomized rats, t o reverse the escape deficit in learned helplessness rats, to antagonize 5HTP-induced head twitches in mice, and to reduce paradoxical sleep in rats (Lloyd et al., 1987). Low doses of fengabine and sodium valproate also decrease immobility in the Porsolt swimming test (Aley and Kulkarni, 1989). Repeated administration of progabide and fengabine significantly increase the binding of L3HI-GABA to GABA, receptors in the frontal cortex of rats, indicating an increase in activity in the GABAergic system (Lloyd et al., 1990).However, an interaction between GABAergic and monoaminergic neurons may also be important in the action of antidepressant substances. GABA,

receptors have been reported to modulate both the release of serotonin from nerve terminals and the activity of Beta-adrenergic adenylate cyclase (Lloyd et al., 1990). For example, baclofen stimulates CAMPproduction, which is significantly reduced in untreated rats given olfactory bulbectomies (Lloyd et al., 1990). Furthermore, fengabide increases the activity of the ventral noradrenergic pathway (Scatton et al., 1987).This effect is inhibited by bicuculline or picrotoxin and is therefore thought to occur via the activation of GABA receptors (Lloyd et al., 1989). Thus, one of the questions presently under investigation is whether GABA mimetics and antidepressant drugs exert their effects through an increase in monoaminergic transmission secondary to increased GABAergic transmission, or whether the GABA system also has an independent role in the regulation of mood. Peptides The category, peptides, includes a large number of substances that, in many cases, are only beginning to be investigated. Of the peptides that have been located in the brain andor CSF, several of them (e.g., vasoactive intestinal polypeptide, somatostatin, thyroidstimulating hormone, corticotropin-releasing hormone, and opioid peptides) have been implicated in the pathophysiology of mood disorders. We describe some of the studies on two peptides, CRH and opioids, that have the most data linking them to mechanisms underlying depression. Corticotropin-releasing hormone Pharmacology of CRH. The synthesis of corticotropin-releasing hormone (CRH),also called corticotropinreleasing factor (CRF), is similar to that of other peptides and unlike monoamine or amino acid transmitter synthesis. Messenger RNA directs the production of a prohormone that is produced on ribosomes in the cell body. Cleavage of the prohormone produces CRH and perhaps other peptides (Thompson et al., 1990). After packaging into vesicles, the hormone is transported to the nerve terminals. CRH is probably inactivated by peptidases, since peptides do not seem to be taken up by nerve terminals as a means of inactivation (Berger and Nemeroff, 1987). CRH receptors have been found in the pituitary gland as well as in many areas of the brain (Aguilera et al., 1990; DeSouza and Isel, 1990). Stimulation of most of these receptors increases levels of the secondary messenger CAMP.However, other intracellular messenger systems may also be involved in the actions of CRH (Aguilera et al., 1990; Battaglia et al., 1990). Biochemicalmeasures in humans and animal models. A preponderance of the published data indicate that CRH levels are elevated in depressed humans as compared with normal controls. Since many of these data derive from studies of hypothalamic-pituitary axis

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functioning, the normal role of CRH in regulating this hormone system is described before the depression data are summarized. CRH has also been reported to regulate complex behavioral and/or physiological behavior in naive animals. CRH, located in the paraventricular neurons of the hypothalamus, is the principal central signal for cleavage of the pituitary prohormone, pro-opiomelanocortin (POMC)into adrenocorticotropic hormone (ACTH) and other peptides, including Beta-lipotropin, Beta-endorphin, and Beta-melanocyte-stimulatinghormone (pMSH) (Gold et al., 1987). Hypothalamic CRH release is regulated, in part, by levels of the glucocorticoid, cortisol in the plasma and brain. Glucocorticoid receptors have been reported in the paraventricular nucleus ( F u e et al., 1987; Liposits et al., 1987b), as well as in the hippocampus, amygdala, and septum (Reichlin, 1987). The regulation of CRH secretion occurs via inhibitory influences of these receptors. In the hippocampus, amygdala, and septum, neurons possessing these receptors are thought to project to the paraventricular nucleus and inhibit CRH production. Studies in rats show that hippocampectomy increases CRH mRNA levels in the paraventricular nucleus (Herman et al., 1989). Cells that contain CRH have also been located in the bed nucleus of the stria terminalis, amygdala, parabrachial nucleus, laterodorsal tegmental nucleus, and brain stem (particularly the locus coeruleus). CRH fibers are found in the cerebral cortex and medial forebrain bundle (Swanson et al., 1983). These neurons are thought to mediate the behaviors seen when CRH is injected intracerebroventricularly into animals. Such injections of CRH cause increased freezing behavior in a novel environment, increased stress-induced fighting, decreased food intake, and sleep disturbances in rodents (Britton et al., 1982; Ehlers et al., 1986; Koob and Britton, 1990; Sutton et al., 1982).Also, the CRH antagonist, Alpha-helical CRH, decreases stress-induced freezing and fighting in rats (Kalin et al., 1988; Koob and Britton, 1990). In chair-restrained monkeys, intracerebroventricular CRH causes struggling, vocalization, and aggressive behavior (Kalin, 1990).Many of these behaviors are similar to those seen in patients with agitated depression. In addition, reserpine (which induces depression in approximately 15%of hypertensive individuals) increases the levels of CRH mRNA in the paraventricular nucleus of rats (Ceccatelli et al., 1990). Depressed patients were reported to have elevated levels of CRH in the CSF as compared with normals (Kilts et al., 1987; Nemeroff et al., 1984). Furthermore, this elevation was hypothesized to be one reason that many patients with depression show increased levels of cortisol in the plasma (Amsterdam et al., 1989; Carroll et al., 1976; Gold et al., 1987). Elevated cortisol levels are thought to contribute to the mechanism whereby a synthetic glucocorticoid, dexamethasone, fails to suppress the secretion of cortisol in some depressed pa-

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tients (“nonsuppressors”). Support for the hypothesis of elevated CRH increasing cortisol levels derives from a study by Schulte et al. (1,985)who administered CRH intraveneously for 24 hr into normal controls. The magnitude of the resulting elevations in plasma and urinary cortisol in these subjects was very similar to that in patients with endogenous depression. While some researchers have not been able to replicate the finding of elevated CRH levels in depressed patients (Gold et al., 1987),it was noted that CRH in the CSF is significantly higher in depressed patients who are dexamethasone nonsuppressors than in dexamethasone suppressors. Although hypothalamic-pituitary-axis (HPA) dysfunction in depressed patients appears t o involve abnormalities in the paraventricular nucleus, with secretion of CRH, studies also implicate abnormalities in the adrenal glands and possibly in the hippocampus. For example, depressed patients have a blunted ACTH response to CRH, but an intact cortisol response to CRH as compared with normal controls (Amsterdam et al., 1989; Von Bardeleben and Holsboer, 1988). These data suggest an enhanced sensitivity of the adrenal gland to ACTH. In support of this hypothesis, depressed patients demonstrated a greater secretion of cortisol from the adrenal cortex following a n infusion of ACTH as compared with controls (Amsterdam et al., 1989; Von Bardeleben and Holsboer, 1988). Also, adrenal gland volume tended to be larger in depressed as compared to normal individuals (Amsterdam et al., 1989). Repeated stress in rats (a model which produces depressed-like behaviors) reduces the number of hippocampal glucocorticoid receptors (Sapolsky et al., 1984a). These hippocampal receptors normally cause inhibition of CRH production in the hypothalamus (Sapolsky et al., 1984b).Thus, depressed patients might also have glucocorticoid receptors in the hippocampus that are downregulated and hence provide less inhibition to the production of CRH. CRH levels would thus be elevated, leading to increases in cortisol levels. Interestingly, the exogenous administration of glucocorticoids to naive rats also decreases the number of cytosolic glucocorticoid receptors in the hippocampus (Sapolsky et al., 1984a; Tornello et al., 1982). Thus, high systemic levels of cortisol, during depression, could also maintain the elevated CRH levels by reducing hippocampal receptor numbers. It is important to note that HPA dysfunction is not unique and therefore not diagnostic, in itself, for depression. Increases in plasma cortisol and/or escape from dexamethasone suppression have also been reported in patients with anorexia nervosa (Gerner and Gwirtsman, 1981) or alcoholism (Stokes, 1973), as well as in Cushings Disease. Likewise, CRH in the CSF was found to be increased in patients with anorexia nervosa (Kaye et al., 1989).

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Effects of antidepressants on neurochemistry. Decreases in plasma cortisol levels and the restoration of dexamethasone suppression have been reported following tricyclic-induced improvement in depressed patients (Carroll et al., 1976; Greden et al., 1983). However, these studies did not address the mechanisms by which the HPA changes occurred following antidepressant treatment. Recently, Pepin et al. (1989) reported that the repeated administration of desipramine, amitriptyline, or maprotiline increased the mRNA of glucocorticoid receptors in hypothalamic and amygdaloid tissue of rats (Table 111). Thus, these antidepressants might increase the feedback inhibition of CRH secretion via an increase in the number of receptors for cortisol. A reduction of CRH secretion would produce less ACTH release from the anterior pituitary, and less cortisol release from the adrenal glands. In contrast to these data and interpretations, Angelucci et a]. (1982) found that another antidepressant, chlorimipramine, reduced the number of [3Hlcorticosterone binding sites in the hippocampus of rats. Thus, an understanding of the potentially conflicting data from these studies awaits further research in this area. Vargas et aI. (1990) reported on another mechanism whereby antidepressants may affect the CRH system. These researchers demonstrated that the anxiolytid antidepressant, alprazolam, decreased CRH levels in the locus coeruleus of rats. Furthermore, locus coeruleus cells are known to be involved in stress reactions that lead to depressed behavior (Weiss et al., 19821,and prolonged stress increases CRH levels in this nucleus (Kilts et al., 1987). Stress and CRH also both increase neuron activity in the locus coeruleus (Valentino et al., 1987; Curtis and Valentino, 1990). Finally, both desipramine and mianserin attenuate the activation of locus coeruleus neurons by hemodynamic stress (Curtis and Valentino, 1990). These antidepressants might therefore be acting via interference with CRH transmission, similar to alprazolam. Although antidepressants may act directly on the CRH system, it is also possible that the drugs affect CRH, secondarily, through monoaminergic neurons. Liposits and co-workersdemonstrated that catecholaminergic (Liposits et al., 1986a), adrenergic (Liposits et al., 1986b1, and serotonergic nerve terminals (Liposits et al., 1987a) all innervate CRH-containing cell bodies in the paraventricular nucleus. While variability in the data exists, many studies have reported that serotonin and acetylcholine stimulate CRH release, while norepinephrine may inhibit the release (see Owens and Nemeroff, 1990, for review). Opioid peptides Pharmacology of the opioid system. The opioid peptides Beta-endorphin and, to a lesser extent, met- and leu-enkephalin, have been implicated in the mecha-

nisms underlying depressed behavior. Like CRH, these peptides are produced from prohormones, which are synthesized by mRNA on ribosomes in the cell body. Beta-endorphin is cleaved from Beta-lipotropin, which is cleaved from the prohormone pro-opiomelanocortin (POMC). Met- and leu-enkephalin are cleaved directly from pro-enkephalin. The two prohormones are contained in separate neuronal systems and, as has been discussed previously, CRH regulates the cleavage of POMC (Berger and Nemeroff, 1987). Both Beta-endorphin and the enkephalins are inactivated by peptidases. Enkephalinase, an enzyme whose subcellular distribution is similar to that of opiate receptors, and aminopeptidase are thought to be important for the degradation of enkephalins (De Felipe et al., 1989; Patey et al., 1981). These enkephalin peptidases act rapidly as compared to the slower degradation of Beta-endorphin. Although several types of opioid receptors have been described (mul, mu2, delta, kappa, sigma, epsilon), the mu and delta types are thought to be important in mood disorders. Beta-endorphin has been reported to show high affinities especially for mu, but also for delta receptors. Leu-enkephalin shows the highest affinity for delta receptors, and met-enkephalin shows affinities for delta and also mu receptors (Berger and Nemeroff, 1987; Holaday et al., 1986; Pasternak, 1987). Biochemical measures in humans and animal models. A great deal of seemingly conflicting data have been reported regarding changes in opioid peptides in depressed humans. Increases, decreases, and no change in opioid activity have all been reported as underlying mechanisms of depression. However, very recently, Biegon and Gross-Isserof (1990) demonstrated that mureceptor binding is increased and delta receptor binding is decreased in the brains of the same suicide victims. These results may clarify some of the previous descrepancies in the data. Before discussing the Biegon and Gross-Isserof data further, some of the conflicting studies will be described. Lindstrom et al. (1978) reported that a fraction of CSF, having opioid receptor activity, was elevated in bipolar patients during the manic phase. However, other studies found no differences in CSF Beta-endorphin immunoreactivity between unipolar or bipolar depressed and controls (Naber et al., 1981).In the plasma, Beta-endorphin was elevated in some depressed patients (Brambilla et al., 1981; Norman et al., 1987; Risch, 1982) and unchanged in others (Emrich et al., 1979; Matthews et al., 1986). Further support for the elevated endorphin hypothesis came from studies showing that, in some depressed patients, neither Betaendorphin nor cortisol were suppressed by dexamethasone (Matthews et al., 1982; Norman et al., 1987).Also, Meador-Woddruff et al. (1987) reported a significant correlation between postdexamethasone Beta-endorphin levels and the severity of depression. On the other hand,

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injections of the opiate antagonist, naloxone, caused the same elevation of plasma cortisol and Beta-endorphin in control and depressed patients (Judd et al., 1981). Behaviorally, naloxone caused dysphoria in some normals (Cohen et al., 1983; Jones and Herning, 1979); it worsened mood (Cohen et al., 1984) or had no effect in depressives (Davis et al., 1979). Some animal studies have also provided support for a hypothesis of increased opioid peptide activity in depression. Maier and colleagues (1980) showed that the inescapable shock paradigm, used to induce a learned helplessness model of depression in rats, also produces analgesia on a tail-flick test. The analgesia is blocked by a long-acting opioid antagonist, naltrexone, suggesting that opioid levels are elevated in the helplessness model. On the other hand, opiates (e.g., opium and morphine), are known to produce euphorogenic effects in normal individuals, and the structurally similar endogenous opioid peptides are thought to have similar behavioral effects (Byck, 1976). Thus, a decrease in activity of the endogenous opioid system has been proposed as a mechanism underlying depression (Emrich, 1982). An animal model, induced by the separation of puppies, young guinea pigs, and chicks from their mothers, supports the hypothesis of decreased opioid levels underlying depressed behavior. These studies demonstrated that both morphine and Beta-endorphin decreased distress vocalizations in these animals, and naloxone reversed this effect (Panksepp et al., 1978). The intravenous administration of Beta-endorphin in humans was reported to produce an improvement of behavioral symptoms (Gerner et al., 1980; Kline et al., 1977; Kline and Lehmann, 1979) or hypomania (Angst et al., 1979) in unipolar and bipolar depressed patients. Nonpeptide opioid compounds, such as cyclazocine (Fink et al., 1970) and buprenorphine (Emrich et al., 1981) were also found to reduce depressive symptoms. However, other studies reported no effects of Betaendorphin on depressive symptoms (Pickar et al., 1981). Likewise, the injection of a stable met-enkephalin analogue, FK-33-824, did not produce significant effects in depressed patients (Jungkunz et al., 1983). Biegon and Gross-Isserof's study (1990) may clarify some of these contradictory data through the demonstration that opioid systems are both increased and decreased in depressed suicidal individuals. Specifically, the reported increase in mu receptor binding may represent regulatory compensation attributable to reduced levels of endogenous agonists, and a decrease in delta receptor binding may result from an increase in agonists for this receptor. These divergent opioid changes occurred in different areas of the brain, which may mediate different behaviors. Also, different types of opioid receptors may be involved in mediating different behaviors. For example, animal models of depressed behavior exhibit changes in locomotor activity (Calde-

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cott-Hazard et al., 1988; Crawley, 1984; Leonard and Tuite, 19811, and locomotion appears t o be mu rather than delta modulated (Caldecott-Hazard and Engel, 1987). Likewise, distress vocalization in separated rat pups appears to be ameliorated by mu- rather than kappa-receptor agonists (Kehoe et al., 1990). On the other hand, some animal models of depressed behavior produce a spinally mediated analgesia (Maier et al., 19801, and delta receptors may be especially important in this type of analgesia (Pasternak, 1987). In addition to the Biegon-Gross Isserof data, other explanations for the contradictions in opioid-depression data may exist. It has been proposed that depressed patients who manifest intense arousal, psychomotor agitation, lack of reactivity of mood, decreased sleep and decreased appetite might have a pathological activation of systems involved in the response to stress. Conversely, patients manifesting fatigue, lethargy, psychomotor retardation, and increased sleep might have a deficiency in those systems involved in the response to stress (Gold et al., 1988; Kling and Kling, in this review, Part I, Caldecott-Hazard et al., 1991). Since opioids are known to be involved in the response to stress, the symptoms in these two types of depressed individuals could involve opposite changes in the opioid system. Of course, technical aspects of the various clinical and animal studies could also contribute to the variability in the data. Effects of antidepressants on neurochemistry. Anumber of studies indicate that various antidepressant treatments may act, a t least in part, through the opioid system (Table 111).For example, in addition to its effects on the noradrenergic, serotonergic, dopaminergic, cholinergic, and GABAergic systems, repeated electroconvulsive shock (ECS) increases brain met-enkephalin levels in rats (Hong et al., 1979) and CSF Beta-endorphin levels in humans (Alexopoulos et al., 1983). Also, Holaday et al. (1986) reported that both mu and delta binding sites in whole brain were increased following repeated ECS. While Antkiewicz-Michaluk et al. (1984) also found increased delta binding sites in the cortex following ECS, delta binding was somewhat reduced in the striatum. Nakata et al., (1985) found that both mu and delta binding were decreased in the striatum, hippocampus and hypothalamus following ECS. Although methodological issues may cloud some of these results, the idea of simultaneous, divergent changes in different opioid receptors following ESC coincides with Biegon and Gross-Isserof's data (1990) in suicide victims. Antidepressant drugs may also act through opioid systems, particularly by increasing opioid activity. For example, the antidepressant effects of chlorimipramine, imipramine, and iprindole (on the forced swimming test in mice) were reversed by the opiate antagonist naloxone (De Felipe et al., 1989; Devoise et al., 1982). Furthermore, chronic tricyclic antidepressant, ipindole, or nomifensin treatment increased enkephalin levels in

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the nucleus accumbens and striatum of the rat (De GABA, and peptides. For example, GABA receptors are Felipe et al., 1985). Finally, tricyclic antidepressants reported to modulate the release of serotonin from nerve and MAOIs were reported to relieve pain in some termi- terminals and the activity of adenylate cyclase linked to nal care patients or in some patients with chronic Beta-adrenergic receptors (Lloyd et al., 1990). The tension headache (reviewed by Feinmann, 1985, and GABAergic system, and especially the serotoninergic Walsh, 1983). Since the patients in these groups were and noradrenergic systems, are implicated in mechadescribed as “not depressed, the analgesic effects of the nisms underlying depressed behavior. On the other drugs were thought to be separable from the antidepres- hand, mu opioid agonists, injected into the ventral sant effects. However, other researchers have not found tegmental area, are reported to enhance local dopamine it possible to separate the analgesic from the mood- release (Klitenick and Kalivas, 1990; Widzowski et al., altering effects of antidepressant drugs (Walsh, 1983). 1990). The ventral tegmental area is known t o be inAnimal studies have shown that tricyclic antidepres- volved in reward behaviors. Opioid and noradrenergic sants produce analgesia on the tail-flick test (De Felipe receptors are reported to be co-localized in the locus et al., 1986) and the footshock-inducedvocalization test coeruleus, and mu or Alpha-2-adrenergic agonists de(Biegon and Samuel, 1980; Eschalier et al., 1981). The crease spontaneous activity in these cells (Harris and analgesia in each of these animal studies was reversed Williams, 1990). The locus coeruleus is known to be by injections of naloxone. Since opioid systems are involved in stress reactions. known to be involved in a variety of behaviors, it is not Other examples of transmitter interactions derive surprising that some antidepressant treatments alter from reports of noradrenergic and serotonergic nerve opioid systems that affect both mood and pain percep- terminals that innervate CRH-containing cells in the paraventricular nucleus (Liposits et al., 1986a,b, 1987a). tion. Serotonin may increase CRH secretion and norepinephConclusions and future directions rine may decrease it (Owens and Nemeroff, 1990).While The data presented in this section indicate that all these studies are informative, they, and other transdopamine, GABA, CRH, and opioid peptides may be mitter interaction studies, need additional investigainvolved in the mechanisms underlying depressed be- tion in normal and depressed animals, and during havior and antidepressant treatments. 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