Life Sciences, Vol . 24, pp . 383-394 Printed in the U .S .A .
Pergamon Press
MINIREVIEW BIOGENIC AMINE HYPOTHESES OF AFFECTIVE DISORDERS David L . Garver, M .D . and John M . Davis, M .D . Department of Psychiatry, Pritzker School of Medicine and Illinois State Psychiatric Institute 1601 West Taylor Street, Chicago, Illinois
Biogenic amine hypotheses of affective disorders have been derived inductively from a series of psychopharmacologic and psychobiologic findings and their apparent association with mood states . Supporting evidence for such hypotheses is indirect . The purpose of this mini-review is to summarize current thinking concerning such indirect evidence which suggests abnormalities of central nervous system (CNS) aminergic systems may be linked to major affective disorders . The biogenic amine hypotheses of affective disorders rest primarily on information arising from three related areas of research . There are observations that certain pharmacologic agents with known effects on central amines alter affective states in man . Second, levels of urinary or cerebrospinal fluid (CSF) metabolites of certain centrally acting amines have been found to be altered in some affective disease patients . Finally, there is evidence from neuroendocrine studies that functional abnormalities of central aminergic systems may exist in affective disorders . Indirect evidence from these three lines of investigation have in general supported aminergic hypotheses of affective disorders which state that some depressive disorders are associated with and may be the result of deficiencies in central catecholamine or indolamine neurotransmission . Some lines of evidence suggest that mania may be accompanied by an increase of catecholamine activity . PHARMACOLOGICALLY INDUCED DEPRESSIVE SYMPTOMS It has been known since the 1950s that certain drugs, especially those used in the treatment of hypertension, induce depressive states in some, but not all patients . Reserpine-induced depressions have occurred in approximately 15X of hypertensioe patients receiving high dosages of the drug (1) . Similar depressive states have been found following a-methyl DOPA . Laboratory studies have shown that reserpine depletes neuronal stores of norepinephrine (NE) (2) and serotonin (5-HT) (3) by impairing the capacity of intraneuronal storage granules to accumulate and protect biogenic amines from oxidative deamination by intraneuronal monoamine oxidase (MAO) (4) . a-Methyl DOPA induces depletion of central catecholamines and 5-HT through synthesis inhibition (5) ; catecholamines are also replaced by a-methyl analogues (5,6) .
0300-9653/79/0129-038302 .00/0 Copyright (c) 1979 Pergamon Press
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PHARMACOLOGIC REVERSAL OF DEPRESSIONS MONOAMINE OXIDASE INHIBITORS (MAOIs) During testing of new antituberculosis drugs, iproniazide was observed to produce mood elevation or euphoria beyond that which would be expected following amelioration of the tuberculosis infections (7) . Subsequent trials of iproniazide in depressed patients showed it to be effective in reversing depressive symptoms (8-10) . Iproniazide was found to inhibit the degredative enzyme MAO (11) . Similar inhibition of MAO has been shown for other antidepressant compounds including tranylcypromine, isocarboxazide, phenelzine, pargyline and nialamide . Such drugs inhibit the activity of MAO isoenzymes which are associated with mitochondria of nerve endings and which intracellularly deaminate the biogenic amines NE, dopamine (DA) and 5-HT . MAOIs cause increases of biogenic amines and decreases of their deaminated metabolites (12, 13) . The degree of inhibition of MAO activity appears to be related to antidepressant effects clinically (14) . TRICYCLIC ANTIDEPRESSANTS In an attempt to develop an antischizophrenic compound similar in structure to chlorpromazine, imipramine was synthesized . Imipramine lacked antischizophrenic properties, but was found to have potent antidepressant effects (15) . Since that time a variety of other tricyclic compounds have been synthesized and have undergone clinical trial . The most commonly used agents with proven efficacy are imipramine, amitriptyline, desipramine, nortriptyline, protriptyline and doxepin (16) . It became immediately apparent that the effective tricyclic antidepressants were not potent monoamine oxidase inhibitors, nor did they increase significantly the quantity of central biogenic amines (1) . It was found that these tricyclic antidepressants by blockade of neurotransmitter reuptake altered the distribution of such amines toward greater amounts of neurotransmitter in the synaptic clefts . Following release of neurotransmitter from aminergic neurons into synaptic clefts and onto post synaptic receptors, the action of the neurotransmitter is terminated primarily by reuptake of the amine from the synaptic cleft by the presynaptic aminergic neuron (17) . A series of studies by various investigators have shown that such reuptake of NE (18-22) and/or 5-HT (21,22) is inhibited by tricyclic antidepressants . Such drugs which diminish the aminergic reuptake process are therefore presumed to increase the quantity of functional neurotransmitter acting upon the post synaptic receptor . Clinically it is apparent that some depressed patients respond to one tricyclic antidepressant, but not to another . One patient may fail to respond to adequate dosages of amitriptyline, but respond well to imipramine ; another patient may fail to respond to imipramine but respond to amitriptyline (23) . Tricyclic antidepressants have recently been examined from the point of view of differential potencies upon NE and 5-HT reuptake mechanisms . Amitriptyline is a relatively pure 5-HT reuptake blocker, whereas desipramine blocks the reuptake only of NE at tissue levels clinically achievable (24) (Table 1) .
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Though there is considerable variation among patients, when amitriptyline is administered the ratio of mean steady state plasma amitriptyline to its also active metabolite nortriptyline is 1 .5 :1 (25) . The predominant pharmacologic effect of amitriptyline administration is therefore the effect of amitriptyline itself on 5-HT reuptake (26] . When imipramine is given to patients the ratio of mean steady state imipramine to its also active metabolite desipramine is 4 .5 :1 (27) . The predominant pharmacologic effect of imipramine administration is therefore the effect of its active metabolite desipramine upon NE reuptake (24) . TABLE 1 Synaptosomal Uptake Inhibition of NE and 5-HT at Clinically Achievable Levels of Tricyclics NE
5-HT
AMITRIPTYLINE
0*
++++**
nortriptyline
(++)
(++)
imipramine
{++)
{+++)
DESIPRAMINE pro a e ac **most active
++++ of activity
0
Some groups of depressed patients fail to respond to amitriptyline but do respond to imipramine or desipramine ; other groups of depressed patients fail to respond to imipramine or desipramine but do respond to amitriptyline (23) . Such differential clinical response to relatively specific 5-HT or NE reuptake inhibitors is pharmacologic evidence supporting two distinct biologic subtypes of depression (24) . The first type may be a NE-related depression which responds to relatively specific pharmacologic intervention which increases synaptic NE, as by desipramine ; the second may be a 5-HT related depression which responds to pharmacologic intervention which increases synaptic 5-HT, as by amitriptyline . It is possible that another pharmacologic agent, d-amphetamine, can be used to identify an imipramine or desipramine responsive depressive subgroup . In a small number of cases oral d-amphetamine is reported to have induced a temporary improvement in depressive symptoms in those depressed patients who subsequently responded to imipramine or desipramine ; d-amphetamine did not appreciably change depressive symptoms in those patients who later failed to respond to these NE reuptake inhibitors (28) . AMINE METABOLITES IN DEPRESSIONS Although behavioral and pharmacologic data in general support hypotheses of amine deficiencies in depressive disorders, such hypotheses do not rest on the mood-altering effects of drugs alone . There is evidence of deficiencies of critical amine metabolites in body fluids of patients with depressive disorders .
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URINARY MHPG Of considerable importance in the study of depressive illnesses was the finding that essentially all central NE is metabolized to 3-methoxy-4-hydroxyphenylglyco-1 (MHPG) (29-31) . MHPG is highly lipid solvable and readily crosses the membranes of the blood-brain-barrier into the peripheral blood and subsequently is excreted in the urine . Other tissues outside the CNS also synthesize and use NE for neurotransmission, then metabolize it to 3-methoxy4-hydroxy-mandelic acid (VMA) and normetanephrine (NMET) as well as MHPG (32) . In a nonhunan primate approximately 50% of urinary MHPG has been shown to arise from central (brain) sources while the remainder arises from the periphery ; in contrast, virtually all VMA, NMET and NE recovered in the urine arises from the periphery (33) . Several investigators have reported that substantial numbers of depressed patients excrete diminished amounts of MHPG in 24 hour urines (34-39), while urinary VMA, NMET and NE in such depressed patients do not differ from controls (34) . Such findings suggest that, while the synthesis and degredation of NE in the periphery is normal, turnover of brain NE is diminished in a significant number of depressed patients . CSF 5-HIAA Examination of the CSF has also shown an important amine metabolite deficiency in some depressed patients . CNS 5-HT is catabolized to the acid metabolite 5-hydroxy-indole-acetic acid (5-HIAA), much of which is released 5-HIAA itself poorly crosses from the CSF to the periphery . It into the CSF . is r~noved from the CSF by an energy dependent transport system which can be inhibited by probenecid, resulting in a turnover-dependent increase in the concentration of CSF 5-HIAA (40,41) . There have been conflicting reports of diminished CSF 5-HIAA in depressed patient populations both at baseline (42-51) and following probenecid administration (41,46,51-54) . Recently investigators have recognized that in depressed patients CSF 5-HIAA concentrations are distributed bimodally both at baseline {55) and following probenecid administration (56) . 26 to 29% of depressed patients fell within the low mode, having diminished CSF 5-HIAA at baseline or following probenecid respectively as compared to controls . Such findings provide evidence for a subgroup of depressed patients with diminished central 5-HT turnover . This smaller subgroup may have been masked in some of the previous studies by greater numbers of depressed patients who failed to have a 5-HT abnormality . It is of particular interest that the group of depressed patients who had low CSF 5-HIAA following probenecid had normal urinary MHPG, whereas the larger number of patients with normal probenecidinduced 5-HIAA accumulation had significantly lower urinary MHPG (56) . Of interest also is the finding that low 5-HIAA depressions appear to benefit clinically from the administration of the 5-HT precursor 5-hydroxy-tryptophane (5-HTP) (57) ; such percursors of 5-HT increase CSF 5-HIAA (58) . Urinary and CSF metabolite studies are strongly supportive of at least two separate subtypes of depressive illness . The first subtype is associated with diminished NE turnover, as identified by diminished urinary MHPG but normal CSF 5-HIAA . The second subtype may be associated with diminished 5-HT turnover as identified by diminished CSF 5-HIAA but normal urinary MHPG .
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NEUROENDOCRINE ABNORMALITIES IN DEPRESSIONS Diminished turnover rates of amines need not be related to functional deficits in such systems . It has therefore been necessary to estimate the presence or absence of functional abnormalities of neurotransmission in depressed patients by other strategies . Neuroendocrine approaches have pro vided indirect evidence of such functional defects . Neuroendocrine strategies are based on the findings that central aminergic neurotransmitter systems, through their synapses in the hypothalamus, modulate the release of polypeptide releasing hormones into the hypophyseal portal sxstem . These polypeptides subsequently regulate the release of growth hormone (GH), adrenocorticotropic hormone (ACTH), etc . from the pituitary (59, 60) . Following insulin-induced hypoglycemia, GH is released into the peripheral circulation . There is evidence that such GH release is regulated in part by central NE systems since adrenergic blockers, such as phentolamine, diminish such insulin-induced release (59) . In many patients with depressive illness insulin-hypoglycemia provokes less GH release than expected from studies~on comparable controls (61,62) . Moreover, the parallel findings of diminished GH response to insulin-hypoglycemia and diminished urinary MHP6 in a small group of depressed patients strongly suggests that a functional deficit of NE neurotransmission occurs in the same patients who have evidence of diminished NE turnover (63) . The GH response to amphetamine is also deficient in many depressed patients (64) . Amphetamine causes release of both NE and DA (65) . Since abnormalities of DA-associated GH release have not been found in depressed patients following 1-DOPA (66,67) or apomorphine (67,68), such low GH responses to amphetamine are also consistent with the hypothesis of deficient central NE systems in some depressed patients . Abnormalities of cortisol control are also present in many depressed patients . Certain depressed patients, but not others, show marked increased pulsatile release of cortisol which results in high plasma cortisol levels, diminished diurnal variation and is usually accompanied by partial or complete failure to suppress plasma cortisol following dexamethazone (69-74) . Plasma cortisol levels are governed primarily by the secretion of ACTH from the anterior pituitary which, in turn is under the influence of the hypothalamic peptide corticotropin-releasing-hormone (CRH) . CRH is released from the median eminance as the result of neurotransmitter activity in the hypothalamus . Animal experiments have shown that CRH is released in response to cholinergic and serotonergic stimulation, while its release is inhibited as a result of a-adrenergic stimulation (60) . If such animal work is applicable to man, diminished central NE activity might well result in increased release of CRH, of ACTH and finally of cortisol release into the peripheral circulation, as well as failure of suppression of cortisol following dexamethazone . There is however fragmentary information suggesting that the neurotransmitter control of the hypothalamic-pituitary-adrenocortical axis may be different in man than in lower species . While the administration of the 5-HT precursor 5-HTP has been shown to increase ACTH clinically (75), methamphetamine also causes an increase in plasma corticosteroids which is inhibited by the a-adrenergic antagonist thymoxamine (76) . Such data suggests that in man NE may be a facilitator rather than an inhibitor of CRH release .
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Elucidation of the biological abnormalities which in man underlie the hypersecretory pattern of cortisol found in some depressed patients await further research . Studies in depressed patients of cortisol secretory patterns in relation to urinary MHPG excretion, CSF 5-HIAA concentrations and differential response patterns to amitriptyline vs imipramine are now underway and may clarify whether such abnormal cortisol patterns are associated with 5-HT vs NE subtyping of depressions . NOREPINE PHRI NE AND SEROTONIN DEPRESSIVE SUBTYPES The data from pharmacologic, from amine metabolite and from growth hormone studies sited above provide evidence for two biologically distinct subtypes of major depressive illness (Table 2) . Patients with norepinephrine depressions appear to excrete diminished amounts of the central NE metabolite MHPG and appear to have diminished response of GH following insulin hypoglycemia . Such NE depressions appear to respond preferentially to tricyclic drugs such as imipramine or desipramine which in patients cause an increase of synaptic NE . Patients with serotonin depressions appear to have diminished CSF 5HIAA, normal or elevated urinary MHPG and normal GH response to insulinhypoglycemia . Such depressions appear to respond preferentially to a tricyclic drug such as amitriptyline which causes an increase in synaptic 5-HT or following administration of the 5-HT precursor 5-HTP . TABLE 2 Evidence for NE and 5-HT Depression Subtypes NE DEPRESSIONS
5-HT DEPRESSIONS
AMINE METABOLITE NE 5-HT
low urinary MHPG nl CSF 5-HIAA
nl urinary MHPG low CSF 5-HIAA
NEUROENDOCRINE GH hypoglyc~nia GH amphetamine
low GH response (low GH response)*
nl GH response (nl GH response)*
good antidepressant response no antidepressant response brief antidepressant response
no antidepressant response good antidepressant response (no antidepressant response)
PHARMACOLOGIC imipramine and desipramine amitriptyline d-amphetamine
from
oug data er~ved such studies indicate two data clusters in depressed populations, these two clusters have not as yet been reported in the same patients who have also been diagnosed as NE or 5-HT depressions on the basis of urinary or CSF metabolites . The text discusses the theoretical issues which would predict such findings in the NE and 5-HT depressions ; these suggestions must be tentative until demonstrated clinically .
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NEUROTRANSMITTER BALANCE AND DEPRESSION Depressive symptoms may be associated not merely with a functional deficit in one neurotransmitter system, but with a consequent disruption of critical balance among multiple neurotransmitter systems within the CNS . There is evidence that patients with depressions which respond to imipramine may be vulnerable to again develop depressive symptoms when central 5-HT synthesis is compromised as a result of treatment with the 5-HT synthesis inhibitor para-chloropher~ylalanine (77) . Functional adequacy of both NE and 5-HT systems appear necessary to maintain antidepressant response induced by imipramine . Patients with depression experience worsening of their symptoms during pharmacologic activation of central cholinergic systems by either physostigmine (78,79) or choline (80) . Cholinergic dominance over NE or 5-HT systems appear to worsen depressive illness . Recently dopaminergic mechanisms have also been implicated as participating in such a critical balance since the dopamine receptor agonist piribedil appears to be effective in reversal of depressive symptoms in some patients (81) . Nomifensen, an antidepressant drug which has dopaminergic agonistic (82,83) as well as NE reuptake inhibitory properties (83) may be particularly useful in depressed patients with psychomotor retardation (84) who also have been shown to have diminished accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF (85) . Such findings may indicate the importance of critical balance among the activities of multiple central neurotransmitter systems whose relative hypo or hyperfunction with respect to NE or 5-HT systems may result in depressive symptoms . THE POSSIBILITY OF ADRENERGIC RECEPTOR ABNORMALITIES IN SOME DEPRESSIONS It is difficult to assess central adrenergic receptor activity directly in depressed patients . Preliminary reports using a neuroendocrine strategy in assessing the a-adrenergic receptor sensitivity have suggested a deficient GH response to clonidine in some depressives (86) . Other pharmacologic data have suggested on the contrary that depression might be accompanied by an increased receptor sensitivity to NE . It has been suggested that the most relevant mechanism of action of tricyclics, MAOIs and ECT on NE systems could be the reduction of NE-sensitive limbic cyclase activity, since the time course of clinical antidepressant response following such chronic drug administration or procedure closely parallels the reduction of such limbic cyclase activity in rats which received similar chronic drug administration or ECT (87,88) . Moreover, iprindole, shown in several double-blind studies to be an effective antidepressant agent (89-92), but pharmacolo ically neither an uptake inhibitor of NE or 5-HT nor an inhibitor of MAO (93,94 , also causes a similar reduction of limbic cyclase activity (87) . Such pharmacologic data might suggest that a supersensitivity of NE receptors in some depressives could be corrected by antidepressant-induced reduction of NE-sensitive limbic cyclase activity . Such a hypothesis of NE receptor supersensitivity in some depressions is not inconsistent with the results of pharmacologic and amine metabolite studies which suggest an NE depression subtype . Supersensitive NE receptors could reasonably be expected to cause feedback inhibition of NE synthesis, resulting in diminished urinary MHPG . On the otherhand, neuroendocrine data, especially the preliminary report of diminished GH response to clonidine in same depressives, appears to be less consistent with a NE receptor supersensitivity hypothesis . The study of receptor function can be expected to be a new focus for neurochemical research in the depressive disorders .
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ANTIDEPRESSANT RESPONSE FOLLOWING NE SYNTHESIS ACCELERATION? Mianserin is a pharmacologic agent which in preliminary studies has been shown to have antidepressant activity comparable to commonly used tricyclic antidepressants (95,96) . Clinically it appear neither to inhibit NE (97,98) or 5-HT (97) uptake, nor does it appear to be a MIAOI (97) . Animal studies indicate that mianserin markedly increases the s nthesis of central NE when administered both acutely (99) and chronically (100, suggesting that the drug may provide more NE for release onto post synaptic adrenergic receptors . Such preliminary work demonstrating a possible mechanism of mianserin's antidepressant action needs considerable clarification in man . Mianserin may well prove to be the prototype of another new class of antidepressant agents which, instead of inhibiting amine reuptake or monoamine oxidase, accelerates the synthesis of NE in order to facilitate central adrenergic neurotransmission . ELECTROCONVULSIVE THERAPY (ECT) IN DEPRESSIONS ECT has been shown to have the greatest efficacy and speed of any tool used in the treatment of depression (101) . Though not controlled for the stress effect of the procedure, animal studies have demonstrated that ECT increases central turnover and brain levels of NE (102) . Clinically, ECT has also been shown to have substantial effect on central NE metabolism, increasing its turnover in recovering depressed patients in the days following ECT treatments as measured by increased urinary MHPG (103) . In a group of depressed patients who had normal basal and probenecid-induced accumulations of 5-HIAA and HVA, the probenecid-induced accumulations of 5-HIAA and HVA following successful ECT treatment of depression did not increase (104), suggesting that ECT is without long term effects on 5-HT and dopamine turnover in the CNS of this patient group . There are no reports concerning the effect of ECT on 5-HT and dopamine turnover in subgroups of depressed patients who prior to treatment showed diminished turnover of these amines . Such findings concerning monoamines and ECT are preliminary at best and need further study before clear conclusions can be drawn . MANIA Amine hypotheses of affective disorders have suggested that a deficiency of central amines, especially NE or 5-HT, is associated with depressive symptomatology, while an excess of catecholamines, particularly NE, may be associated with mania . Central NE turnover during the course of bipolar illness have been studied by monitoring urinary MHPG, and index of central NE turnover . In patients who are rapidly cycling from mania to depression several authors have described diminished MHPG during the depressed phase of the illness with higher MHPG in the manic phase (105,106) . During mania, however, MHPG excretion is essentially normal rather than high (39) . It is also of interest that in mixed depression-and-mania MHPG is generally reduced (unpublished data) . While depressive symptoms appear well correlated with diminished MHPG, manic symptoms show no such correlation . Blockade of NE synthesis with the dopamine-ß-oxidase inhibitor, fusaric acid, which decreases central NE, does not relieve mania (107) . However, blockade of catecholamine synthesis several steps earlier, at the tyrosine hydroxylase step with a-methyl-para-tyrosine, does relieve manic symptoms (108) . Such blockade at the tyrosine hydroxylase step decreases not only NE, but also DA receptor blocking agents are effective in the treatment of central DA . mania and these neuroleptic drugs were the treatment of choice before the use
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of lithium . Furthermore, mania can be interrupted not only by neuroleptics, but also by physostigmine, an anticholinesterase inhibitor, which raises the level of acetylcholine within the CNS (109) . Such findings suggest that critical balances between neurotransmitter systems exist within the brain . Underlying mania may be a relative predominance of DA systems . This may be due to alterations in DA neurons or receptors, or perhaps to deficiencies of cholinergic function . The data, in toto suggest that while diminished NE may be associated with depressive symptom~n bipolar illness, another abnormality, perhaps associated with predominance of DA systems, may be associated with manic episodes . THE POSSIBILITY OF MEMBRANE ABNORMALITIES IN MANIC PATIENTS Attention has recently focused upon an impaired ability of many manic patients (110,111) and certain of their first degree relatives (111) to extrude the lithium ion from their red blood cells . In vitro studies of red cells have demonstrated that a substantial number of rtianic patients and their first degree relatives have a m~nbrane abnormality of sodium (and lithium) exchange associated with a phloretin-sensitive pathway (112) . If such a membrane ion exchange abnormality is also present in CNS neurons of such patients, there may be significant impairment of the ionic fluxes underlying depolarization and repolarization of such neurons . Firing rates of a variety of affected cells may be altered and the critical balances among the activities of various neurotransmitter systans disrupted . Such disruption of balance may lead clinically to overt affective symptomatology . The accumulation of intracellular lithiun in such patients may compensate for ion exchange abnormalities and permit restoration of physiological feedback modulation and balance . While abnormalities of ion exchange across menbranes in some manic patients is an intriguing concept, data suggesting such an abnormality is very preliminary at best, but can be expected to renew interest in the study of electrolyte abnormalities in affective illnesses . SUMMARY Many lines of evidence suggest that affective disease is a heterogenous group of disorders . Pharmacologic, amine metabolite and neuroendocrine studies have aided in the tentative identification of two subtypes of depres sive illness . One subtype may show an abnormality of central NE systems ; the other, an abnormality of central 5-HT systems . Manic patients appear to manifest abnormalities of multiple systems biologically which may be related to a disturbance of ion exchange in a variety of cells both within and outside of the CNS . The understanding of these processes is far from complete and are the subject of continued scrutiny . REFERENCES W .E .Bunney, J .M .Davis, Arch . Gen . Ps chiat . 13 484-494 (1965) . M .Holzbauer, M .Vogt, J .~feuroc~. 1 - 1 1~6) . A .Pletscher, P .A .Shoré, B .B .Brodie, Science 122 374-375 (1955) . L .Stjarne, Acta ~Ph~siol . Scand . suppT~f$~9~6 (1964) . M .Henning, Acta yPh siol . Sch suppl 3~ 1-37 (1969) . J .R .Cooper, F .E .Bloom, R .H .Ro ,The Biochemical Basis of Neuro harma~colo , (pp . 141, 160, 163, 190-1~ xfo Press, New work 197 7 .I J .Selikoff, E .H .Robitzek, G .G .Ornstein, uart . Bull . Sea View Hosp . 13 17 (1952) . 1. 2. 3. 4. 5. 6.
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Pergamon Press
MINIREVIEW BIOGENIC AMINE HYPOTHESES OF AFFECTIVE DISORDERS David L . Garver, M .D . and John M . Davis, M .D . Department of Psychiatry, Pritzker School of Medicine and Illinois State Psychiatric Institute 1601 West Taylor Street, Chicago, Illinois
Biogenic amine hypotheses of affective disorders have been derived inductively from a series of psychopharmacologic and psychobiologic findings and their apparent association with mood states . Supporting evidence for such hypotheses is indirect . The purpose of this mini-review is to summarize current thinking concerning such indirect evidence which suggests abnormalities of central nervous system (CNS) aminergic systems may be linked to major affective disorders . The biogenic amine hypotheses of affective disorders rest primarily on information arising from three related areas of research . There are observations that certain pharmacologic agents with known effects on central amines alter affective states in man . Second, levels of urinary or cerebrospinal fluid (CSF) metabolites of certain centrally acting amines have been found to be altered in some affective disease patients . Finally, there is evidence from neuroendocrine studies that functional abnormalities of central aminergic systems may exist in affective disorders . Indirect evidence from these three lines of investigation have in general supported aminergic hypotheses of affective disorders which state that some depressive disorders are associated with and may be the result of deficiencies in central catecholamine or indolamine neurotransmission . Some lines of evidence suggest that mania may be accompanied by an increase of catecholamine activity . PHARMACOLOGICALLY INDUCED DEPRESSIVE SYMPTOMS It has been known since the 1950s that certain drugs, especially those used in the treatment of hypertension, induce depressive states in some, but not all patients . Reserpine-induced depressions have occurred in approximately 15X of hypertensioe patients receiving high dosages of the drug (1) . Similar depressive states have been found following a-methyl DOPA . Laboratory studies have shown that reserpine depletes neuronal stores of norepinephrine (NE) (2) and serotonin (5-HT) (3) by impairing the capacity of intraneuronal storage granules to accumulate and protect biogenic amines from oxidative deamination by intraneuronal monoamine oxidase (MAO) (4) . a-Methyl DOPA induces depletion of central catecholamines and 5-HT through synthesis inhibition (5) ; catecholamines are also replaced by a-methyl analogues (5,6) .
0300-9653/79/0129-038302 .00/0 Copyright (c) 1979 Pergamon Press
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PHARMACOLOGIC REVERSAL OF DEPRESSIONS MONOAMINE OXIDASE INHIBITORS (MAOIs) During testing of new antituberculosis drugs, iproniazide was observed to produce mood elevation or euphoria beyond that which would be expected following amelioration of the tuberculosis infections (7) . Subsequent trials of iproniazide in depressed patients showed it to be effective in reversing depressive symptoms (8-10) . Iproniazide was found to inhibit the degredative enzyme MAO (11) . Similar inhibition of MAO has been shown for other antidepressant compounds including tranylcypromine, isocarboxazide, phenelzine, pargyline and nialamide . Such drugs inhibit the activity of MAO isoenzymes which are associated with mitochondria of nerve endings and which intracellularly deaminate the biogenic amines NE, dopamine (DA) and 5-HT . MAOIs cause increases of biogenic amines and decreases of their deaminated metabolites (12, 13) . The degree of inhibition of MAO activity appears to be related to antidepressant effects clinically (14) . TRICYCLIC ANTIDEPRESSANTS In an attempt to develop an antischizophrenic compound similar in structure to chlorpromazine, imipramine was synthesized . Imipramine lacked antischizophrenic properties, but was found to have potent antidepressant effects (15) . Since that time a variety of other tricyclic compounds have been synthesized and have undergone clinical trial . The most commonly used agents with proven efficacy are imipramine, amitriptyline, desipramine, nortriptyline, protriptyline and doxepin (16) . It became immediately apparent that the effective tricyclic antidepressants were not potent monoamine oxidase inhibitors, nor did they increase significantly the quantity of central biogenic amines (1) . It was found that these tricyclic antidepressants by blockade of neurotransmitter reuptake altered the distribution of such amines toward greater amounts of neurotransmitter in the synaptic clefts . Following release of neurotransmitter from aminergic neurons into synaptic clefts and onto post synaptic receptors, the action of the neurotransmitter is terminated primarily by reuptake of the amine from the synaptic cleft by the presynaptic aminergic neuron (17) . A series of studies by various investigators have shown that such reuptake of NE (18-22) and/or 5-HT (21,22) is inhibited by tricyclic antidepressants . Such drugs which diminish the aminergic reuptake process are therefore presumed to increase the quantity of functional neurotransmitter acting upon the post synaptic receptor . Clinically it is apparent that some depressed patients respond to one tricyclic antidepressant, but not to another . One patient may fail to respond to adequate dosages of amitriptyline, but respond well to imipramine ; another patient may fail to respond to imipramine but respond to amitriptyline (23) . Tricyclic antidepressants have recently been examined from the point of view of differential potencies upon NE and 5-HT reuptake mechanisms . Amitriptyline is a relatively pure 5-HT reuptake blocker, whereas desipramine blocks the reuptake only of NE at tissue levels clinically achievable (24) (Table 1) .
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Though there is considerable variation among patients, when amitriptyline is administered the ratio of mean steady state plasma amitriptyline to its also active metabolite nortriptyline is 1 .5 :1 (25) . The predominant pharmacologic effect of amitriptyline administration is therefore the effect of amitriptyline itself on 5-HT reuptake (26] . When imipramine is given to patients the ratio of mean steady state imipramine to its also active metabolite desipramine is 4 .5 :1 (27) . The predominant pharmacologic effect of imipramine administration is therefore the effect of its active metabolite desipramine upon NE reuptake (24) . TABLE 1 Synaptosomal Uptake Inhibition of NE and 5-HT at Clinically Achievable Levels of Tricyclics NE
5-HT
AMITRIPTYLINE
0*
++++**
nortriptyline
(++)
(++)
imipramine
{++)
{+++)
DESIPRAMINE pro a e ac **most active
++++ of activity
0
Some groups of depressed patients fail to respond to amitriptyline but do respond to imipramine or desipramine ; other groups of depressed patients fail to respond to imipramine or desipramine but do respond to amitriptyline (23) . Such differential clinical response to relatively specific 5-HT or NE reuptake inhibitors is pharmacologic evidence supporting two distinct biologic subtypes of depression (24) . The first type may be a NE-related depression which responds to relatively specific pharmacologic intervention which increases synaptic NE, as by desipramine ; the second may be a 5-HT related depression which responds to pharmacologic intervention which increases synaptic 5-HT, as by amitriptyline . It is possible that another pharmacologic agent, d-amphetamine, can be used to identify an imipramine or desipramine responsive depressive subgroup . In a small number of cases oral d-amphetamine is reported to have induced a temporary improvement in depressive symptoms in those depressed patients who subsequently responded to imipramine or desipramine ; d-amphetamine did not appreciably change depressive symptoms in those patients who later failed to respond to these NE reuptake inhibitors (28) . AMINE METABOLITES IN DEPRESSIONS Although behavioral and pharmacologic data in general support hypotheses of amine deficiencies in depressive disorders, such hypotheses do not rest on the mood-altering effects of drugs alone . There is evidence of deficiencies of critical amine metabolites in body fluids of patients with depressive disorders .
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URINARY MHPG Of considerable importance in the study of depressive illnesses was the finding that essentially all central NE is metabolized to 3-methoxy-4-hydroxyphenylglyco-1 (MHPG) (29-31) . MHPG is highly lipid solvable and readily crosses the membranes of the blood-brain-barrier into the peripheral blood and subsequently is excreted in the urine . Other tissues outside the CNS also synthesize and use NE for neurotransmission, then metabolize it to 3-methoxy4-hydroxy-mandelic acid (VMA) and normetanephrine (NMET) as well as MHPG (32) . In a nonhunan primate approximately 50% of urinary MHPG has been shown to arise from central (brain) sources while the remainder arises from the periphery ; in contrast, virtually all VMA, NMET and NE recovered in the urine arises from the periphery (33) . Several investigators have reported that substantial numbers of depressed patients excrete diminished amounts of MHPG in 24 hour urines (34-39), while urinary VMA, NMET and NE in such depressed patients do not differ from controls (34) . Such findings suggest that, while the synthesis and degredation of NE in the periphery is normal, turnover of brain NE is diminished in a significant number of depressed patients . CSF 5-HIAA Examination of the CSF has also shown an important amine metabolite deficiency in some depressed patients . CNS 5-HT is catabolized to the acid metabolite 5-hydroxy-indole-acetic acid (5-HIAA), much of which is released 5-HIAA itself poorly crosses from the CSF to the periphery . It into the CSF . is r~noved from the CSF by an energy dependent transport system which can be inhibited by probenecid, resulting in a turnover-dependent increase in the concentration of CSF 5-HIAA (40,41) . There have been conflicting reports of diminished CSF 5-HIAA in depressed patient populations both at baseline (42-51) and following probenecid administration (41,46,51-54) . Recently investigators have recognized that in depressed patients CSF 5-HIAA concentrations are distributed bimodally both at baseline {55) and following probenecid administration (56) . 26 to 29% of depressed patients fell within the low mode, having diminished CSF 5-HIAA at baseline or following probenecid respectively as compared to controls . Such findings provide evidence for a subgroup of depressed patients with diminished central 5-HT turnover . This smaller subgroup may have been masked in some of the previous studies by greater numbers of depressed patients who failed to have a 5-HT abnormality . It is of particular interest that the group of depressed patients who had low CSF 5-HIAA following probenecid had normal urinary MHPG, whereas the larger number of patients with normal probenecidinduced 5-HIAA accumulation had significantly lower urinary MHPG (56) . Of interest also is the finding that low 5-HIAA depressions appear to benefit clinically from the administration of the 5-HT precursor 5-hydroxy-tryptophane (5-HTP) (57) ; such percursors of 5-HT increase CSF 5-HIAA (58) . Urinary and CSF metabolite studies are strongly supportive of at least two separate subtypes of depressive illness . The first subtype is associated with diminished NE turnover, as identified by diminished urinary MHPG but normal CSF 5-HIAA . The second subtype may be associated with diminished 5-HT turnover as identified by diminished CSF 5-HIAA but normal urinary MHPG .
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NEUROENDOCRINE ABNORMALITIES IN DEPRESSIONS Diminished turnover rates of amines need not be related to functional deficits in such systems . It has therefore been necessary to estimate the presence or absence of functional abnormalities of neurotransmission in depressed patients by other strategies . Neuroendocrine approaches have pro vided indirect evidence of such functional defects . Neuroendocrine strategies are based on the findings that central aminergic neurotransmitter systems, through their synapses in the hypothalamus, modulate the release of polypeptide releasing hormones into the hypophyseal portal sxstem . These polypeptides subsequently regulate the release of growth hormone (GH), adrenocorticotropic hormone (ACTH), etc . from the pituitary (59, 60) . Following insulin-induced hypoglycemia, GH is released into the peripheral circulation . There is evidence that such GH release is regulated in part by central NE systems since adrenergic blockers, such as phentolamine, diminish such insulin-induced release (59) . In many patients with depressive illness insulin-hypoglycemia provokes less GH release than expected from studies~on comparable controls (61,62) . Moreover, the parallel findings of diminished GH response to insulin-hypoglycemia and diminished urinary MHP6 in a small group of depressed patients strongly suggests that a functional deficit of NE neurotransmission occurs in the same patients who have evidence of diminished NE turnover (63) . The GH response to amphetamine is also deficient in many depressed patients (64) . Amphetamine causes release of both NE and DA (65) . Since abnormalities of DA-associated GH release have not been found in depressed patients following 1-DOPA (66,67) or apomorphine (67,68), such low GH responses to amphetamine are also consistent with the hypothesis of deficient central NE systems in some depressed patients . Abnormalities of cortisol control are also present in many depressed patients . Certain depressed patients, but not others, show marked increased pulsatile release of cortisol which results in high plasma cortisol levels, diminished diurnal variation and is usually accompanied by partial or complete failure to suppress plasma cortisol following dexamethazone (69-74) . Plasma cortisol levels are governed primarily by the secretion of ACTH from the anterior pituitary which, in turn is under the influence of the hypothalamic peptide corticotropin-releasing-hormone (CRH) . CRH is released from the median eminance as the result of neurotransmitter activity in the hypothalamus . Animal experiments have shown that CRH is released in response to cholinergic and serotonergic stimulation, while its release is inhibited as a result of a-adrenergic stimulation (60) . If such animal work is applicable to man, diminished central NE activity might well result in increased release of CRH, of ACTH and finally of cortisol release into the peripheral circulation, as well as failure of suppression of cortisol following dexamethazone . There is however fragmentary information suggesting that the neurotransmitter control of the hypothalamic-pituitary-adrenocortical axis may be different in man than in lower species . While the administration of the 5-HT precursor 5-HTP has been shown to increase ACTH clinically (75), methamphetamine also causes an increase in plasma corticosteroids which is inhibited by the a-adrenergic antagonist thymoxamine (76) . Such data suggests that in man NE may be a facilitator rather than an inhibitor of CRH release .
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Elucidation of the biological abnormalities which in man underlie the hypersecretory pattern of cortisol found in some depressed patients await further research . Studies in depressed patients of cortisol secretory patterns in relation to urinary MHPG excretion, CSF 5-HIAA concentrations and differential response patterns to amitriptyline vs imipramine are now underway and may clarify whether such abnormal cortisol patterns are associated with 5-HT vs NE subtyping of depressions . NOREPINE PHRI NE AND SEROTONIN DEPRESSIVE SUBTYPES The data from pharmacologic, from amine metabolite and from growth hormone studies sited above provide evidence for two biologically distinct subtypes of major depressive illness (Table 2) . Patients with norepinephrine depressions appear to excrete diminished amounts of the central NE metabolite MHPG and appear to have diminished response of GH following insulin hypoglycemia . Such NE depressions appear to respond preferentially to tricyclic drugs such as imipramine or desipramine which in patients cause an increase of synaptic NE . Patients with serotonin depressions appear to have diminished CSF 5HIAA, normal or elevated urinary MHPG and normal GH response to insulinhypoglycemia . Such depressions appear to respond preferentially to a tricyclic drug such as amitriptyline which causes an increase in synaptic 5-HT or following administration of the 5-HT precursor 5-HTP . TABLE 2 Evidence for NE and 5-HT Depression Subtypes NE DEPRESSIONS
5-HT DEPRESSIONS
AMINE METABOLITE NE 5-HT
low urinary MHPG nl CSF 5-HIAA
nl urinary MHPG low CSF 5-HIAA
NEUROENDOCRINE GH hypoglyc~nia GH amphetamine
low GH response (low GH response)*
nl GH response (nl GH response)*
good antidepressant response no antidepressant response brief antidepressant response
no antidepressant response good antidepressant response (no antidepressant response)
PHARMACOLOGIC imipramine and desipramine amitriptyline d-amphetamine
from
oug data er~ved such studies indicate two data clusters in depressed populations, these two clusters have not as yet been reported in the same patients who have also been diagnosed as NE or 5-HT depressions on the basis of urinary or CSF metabolites . The text discusses the theoretical issues which would predict such findings in the NE and 5-HT depressions ; these suggestions must be tentative until demonstrated clinically .
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NEUROTRANSMITTER BALANCE AND DEPRESSION Depressive symptoms may be associated not merely with a functional deficit in one neurotransmitter system, but with a consequent disruption of critical balance among multiple neurotransmitter systems within the CNS . There is evidence that patients with depressions which respond to imipramine may be vulnerable to again develop depressive symptoms when central 5-HT synthesis is compromised as a result of treatment with the 5-HT synthesis inhibitor para-chloropher~ylalanine (77) . Functional adequacy of both NE and 5-HT systems appear necessary to maintain antidepressant response induced by imipramine . Patients with depression experience worsening of their symptoms during pharmacologic activation of central cholinergic systems by either physostigmine (78,79) or choline (80) . Cholinergic dominance over NE or 5-HT systems appear to worsen depressive illness . Recently dopaminergic mechanisms have also been implicated as participating in such a critical balance since the dopamine receptor agonist piribedil appears to be effective in reversal of depressive symptoms in some patients (81) . Nomifensen, an antidepressant drug which has dopaminergic agonistic (82,83) as well as NE reuptake inhibitory properties (83) may be particularly useful in depressed patients with psychomotor retardation (84) who also have been shown to have diminished accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF (85) . Such findings may indicate the importance of critical balance among the activities of multiple central neurotransmitter systems whose relative hypo or hyperfunction with respect to NE or 5-HT systems may result in depressive symptoms . THE POSSIBILITY OF ADRENERGIC RECEPTOR ABNORMALITIES IN SOME DEPRESSIONS It is difficult to assess central adrenergic receptor activity directly in depressed patients . Preliminary reports using a neuroendocrine strategy in assessing the a-adrenergic receptor sensitivity have suggested a deficient GH response to clonidine in some depressives (86) . Other pharmacologic data have suggested on the contrary that depression might be accompanied by an increased receptor sensitivity to NE . It has been suggested that the most relevant mechanism of action of tricyclics, MAOIs and ECT on NE systems could be the reduction of NE-sensitive limbic cyclase activity, since the time course of clinical antidepressant response following such chronic drug administration or procedure closely parallels the reduction of such limbic cyclase activity in rats which received similar chronic drug administration or ECT (87,88) . Moreover, iprindole, shown in several double-blind studies to be an effective antidepressant agent (89-92), but pharmacolo ically neither an uptake inhibitor of NE or 5-HT nor an inhibitor of MAO (93,94 , also causes a similar reduction of limbic cyclase activity (87) . Such pharmacologic data might suggest that a supersensitivity of NE receptors in some depressives could be corrected by antidepressant-induced reduction of NE-sensitive limbic cyclase activity . Such a hypothesis of NE receptor supersensitivity in some depressions is not inconsistent with the results of pharmacologic and amine metabolite studies which suggest an NE depression subtype . Supersensitive NE receptors could reasonably be expected to cause feedback inhibition of NE synthesis, resulting in diminished urinary MHPG . On the otherhand, neuroendocrine data, especially the preliminary report of diminished GH response to clonidine in same depressives, appears to be less consistent with a NE receptor supersensitivity hypothesis . The study of receptor function can be expected to be a new focus for neurochemical research in the depressive disorders .
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ANTIDEPRESSANT RESPONSE FOLLOWING NE SYNTHESIS ACCELERATION? Mianserin is a pharmacologic agent which in preliminary studies has been shown to have antidepressant activity comparable to commonly used tricyclic antidepressants (95,96) . Clinically it appear neither to inhibit NE (97,98) or 5-HT (97) uptake, nor does it appear to be a MIAOI (97) . Animal studies indicate that mianserin markedly increases the s nthesis of central NE when administered both acutely (99) and chronically (100, suggesting that the drug may provide more NE for release onto post synaptic adrenergic receptors . Such preliminary work demonstrating a possible mechanism of mianserin's antidepressant action needs considerable clarification in man . Mianserin may well prove to be the prototype of another new class of antidepressant agents which, instead of inhibiting amine reuptake or monoamine oxidase, accelerates the synthesis of NE in order to facilitate central adrenergic neurotransmission . ELECTROCONVULSIVE THERAPY (ECT) IN DEPRESSIONS ECT has been shown to have the greatest efficacy and speed of any tool used in the treatment of depression (101) . Though not controlled for the stress effect of the procedure, animal studies have demonstrated that ECT increases central turnover and brain levels of NE (102) . Clinically, ECT has also been shown to have substantial effect on central NE metabolism, increasing its turnover in recovering depressed patients in the days following ECT treatments as measured by increased urinary MHPG (103) . In a group of depressed patients who had normal basal and probenecid-induced accumulations of 5-HIAA and HVA, the probenecid-induced accumulations of 5-HIAA and HVA following successful ECT treatment of depression did not increase (104), suggesting that ECT is without long term effects on 5-HT and dopamine turnover in the CNS of this patient group . There are no reports concerning the effect of ECT on 5-HT and dopamine turnover in subgroups of depressed patients who prior to treatment showed diminished turnover of these amines . Such findings concerning monoamines and ECT are preliminary at best and need further study before clear conclusions can be drawn . MANIA Amine hypotheses of affective disorders have suggested that a deficiency of central amines, especially NE or 5-HT, is associated with depressive symptomatology, while an excess of catecholamines, particularly NE, may be associated with mania . Central NE turnover during the course of bipolar illness have been studied by monitoring urinary MHPG, and index of central NE turnover . In patients who are rapidly cycling from mania to depression several authors have described diminished MHPG during the depressed phase of the illness with higher MHPG in the manic phase (105,106) . During mania, however, MHPG excretion is essentially normal rather than high (39) . It is also of interest that in mixed depression-and-mania MHPG is generally reduced (unpublished data) . While depressive symptoms appear well correlated with diminished MHPG, manic symptoms show no such correlation . Blockade of NE synthesis with the dopamine-ß-oxidase inhibitor, fusaric acid, which decreases central NE, does not relieve mania (107) . However, blockade of catecholamine synthesis several steps earlier, at the tyrosine hydroxylase step with a-methyl-para-tyrosine, does relieve manic symptoms (108) . Such blockade at the tyrosine hydroxylase step decreases not only NE, but also DA receptor blocking agents are effective in the treatment of central DA . mania and these neuroleptic drugs were the treatment of choice before the use
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of lithium . Furthermore, mania can be interrupted not only by neuroleptics, but also by physostigmine, an anticholinesterase inhibitor, which raises the level of acetylcholine within the CNS (109) . Such findings suggest that critical balances between neurotransmitter systems exist within the brain . Underlying mania may be a relative predominance of DA systems . This may be due to alterations in DA neurons or receptors, or perhaps to deficiencies of cholinergic function . The data, in toto suggest that while diminished NE may be associated with depressive symptom~n bipolar illness, another abnormality, perhaps associated with predominance of DA systems, may be associated with manic episodes . THE POSSIBILITY OF MEMBRANE ABNORMALITIES IN MANIC PATIENTS Attention has recently focused upon an impaired ability of many manic patients (110,111) and certain of their first degree relatives (111) to extrude the lithium ion from their red blood cells . In vitro studies of red cells have demonstrated that a substantial number of rtianic patients and their first degree relatives have a m~nbrane abnormality of sodium (and lithium) exchange associated with a phloretin-sensitive pathway (112) . If such a membrane ion exchange abnormality is also present in CNS neurons of such patients, there may be significant impairment of the ionic fluxes underlying depolarization and repolarization of such neurons . Firing rates of a variety of affected cells may be altered and the critical balances among the activities of various neurotransmitter systans disrupted . Such disruption of balance may lead clinically to overt affective symptomatology . The accumulation of intracellular lithiun in such patients may compensate for ion exchange abnormalities and permit restoration of physiological feedback modulation and balance . While abnormalities of ion exchange across menbranes in some manic patients is an intriguing concept, data suggesting such an abnormality is very preliminary at best, but can be expected to renew interest in the study of electrolyte abnormalities in affective illnesses . SUMMARY Many lines of evidence suggest that affective disease is a heterogenous group of disorders . Pharmacologic, amine metabolite and neuroendocrine studies have aided in the tentative identification of two subtypes of depres sive illness . One subtype may show an abnormality of central NE systems ; the other, an abnormality of central 5-HT systems . Manic patients appear to manifest abnormalities of multiple systems biologically which may be related to a disturbance of ion exchange in a variety of cells both within and outside of the CNS . The understanding of these processes is far from complete and are the subject of continued scrutiny . REFERENCES W .E .Bunney, J .M .Davis, Arch . Gen . Ps chiat . 13 484-494 (1965) . M .Holzbauer, M .Vogt, J .~feuroc~. 1 - 1 1~6) . A .Pletscher, P .A .Shoré, B .B .Brodie, Science 122 374-375 (1955) . L .Stjarne, Acta ~Ph~siol . Scand . suppT~f$~9~6 (1964) . M .Henning, Acta yPh siol . Sch suppl 3~ 1-37 (1969) . J .R .Cooper, F .E .Bloom, R .H .Ro ,The Biochemical Basis of Neuro harma~colo , (pp . 141, 160, 163, 190-1~ xfo Press, New work 197 7 .I J .Selikoff, E .H .Robitzek, G .G .Ornstein, uart . Bull . Sea View Hosp . 13 17 (1952) . 1. 2. 3. 4. 5. 6.
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