SPECIAL ARTICLE Neurochemistry and Child and Adolescent Psychiatry GRAHAM A. ROGENESS, M.D., MARTIN A. JAVORS, PH.D.,

AND

STEVEN R. PLISZKA, M.D.

Abstract. This article reviews some of the neurochemistry and neurophysiology of three neurotransmitters: dopamine, norepinephrine, and serotonin. These neurotransmitters are selected because they appear to be involved in the regulation of several important behavioral systems that help regulate the interaction of the organism with its external environment, because many of the psychotropic drugs' modes of action may be result from their effects on these neurotransmitter systems, and because the majority of neurochemical studies in child psychiatry have focused on these three neurotransmitters. After the review of the neurotransmitter systems, neurochemical studies in several child psychiatric disorders are reviewed to illustrate possible biochemicallbehavioral relationships in child psychiatry. J. Am. Acad. Child Adolesc. Psychiatry, 1992,31,5:765-781. Key Words: dopamine, norepinephrine, serotonin, child psychiatry. There are at least 30 neurotransmitters (NTs) in the CNS (Coyle, 1985), most or all of which may have varying roles in behavioral patterns seen in psychiatric disorders. In this article, we will be reviewing three NTs: norepinephrine (NE), dopamine (DA), and serotonin (5HT), and ways in which their function may be important in child psychiatric disorders. These three are selected because 1) they appear to be involved in the regulation of several important behavioral systems that help regulate the interaction of the organism with its external environment; 2) many of the psychotropic drugs' modes of action may be due to their effects on these NTs, and 3) the majority of neurochemical studies in child psychiatry have focused on these three NTs. Limiting this review to these three NTs and not discussing some of their interactions with and regulation by other NTs is an oversimplification, but one that facilitates the presentation and understanding of the information. In this report, we will describe some of the ways in which these three NTs are regulated neurochemically, and how they theoretically may be involved in the function and/or regulation of several behavioral systems. Based on these theories, we will make hypotheses regarding how different relationships among these three NT systems may affect behavior and relate to psychiatric disorders in children. We will then summarize neurochemical methods currently used to try to obtain a measure of the functioning of these NT systems and review neurochemical studies in several child

Accepted October 9, 1991. Dr. Rogeness is Clinical Professor of Psychiatry, Dr. Javors is Associate Professor, and Dr. Pltszka is Assistant Professor ofPsychiatry, Department ofPsychiatry, The University ofTexas Health Science Center at San Antonio. Dr. Rogeness is also Associate Medical Director at Southwest Neuropsychiatric Institute. This work was supported by grants from the Meadows Foundation , and the San Antonio Area Foundation. Reprint requests to Dr. Rogeness, Department of Psychiatry, The University ofTexas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio TX 78284-7792. 0890-8567/92/3505-0765$03.00/0©1992 by the American Academy of Child and Adolescent Psychiatry. J. Am. Acad. Child Adolesc. Psychiatry, 31:5, September 1992

psychiatric disorders, examining whether or not the data provide any support for the proposed hypotheses.

Regulation of Neurotransmitter Function The activity of a neurotransmitter at a synapse is regulated in multiple ways. These ways suggest that there are many safeguards within the brain to keep systems in balance. For the sake of description, we will divide regulation into "within system" regulation and "outside system" regulation. Within System Regulation NTs have mechanisms for self-regulation. For example, availability and effectiveness of 5HT at a synapse would be influenced by precursor availability, synthesizing enzymes, metabolic enzymes, release and reuptake of 5HT at the synapse, and pre- and postsynaptic receptor function. Table 1 shows these steps for DA, NE, and 5HT, and Table 2 shows steps in chemical transmission at the synapse. There are pharmacological agents that alter function at each of these steps. For example, reserpine interferes with storage of NTs in synaptic vesicles, MAO inhibitors inhibit their degradation by MAO, tricyclic antidepressants inhibit the reuptake by nerve terminals, clonidine stimulates presynaptic a2 receptors to inhibit release of NE, neuroleptics block postsynaptic DA receptors, and lithium affects the second messenger phosphatidylinositol system. One can look at the many steps in regulation as either many possible ways for a system to get out of balance or many ways in which a system may compensate if one part of the system gets out of balance. The system may also be able to be in balance at normal activity, but be unable to stay in balance during increased activity (when stressed). For example, sufficient precursor may be available to maintain balance during normal activity, but not during increased activity, therefore depleting the availability of NT and interfering with the optimum functioning of the system.

Outside System Regulation A neuron using a specific NT connects with neurons using 765

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1. Neurotransmitter Metabolic and Receptor Characteristics

Dopamine

Norepinephrine

Serotonin

Precursors Synthetic enzymes (rate-limiting) Storage Catabolic enzymes Intracellular Extracellular Receptors Presynaptic Postsynaptic

Phenylalanine, tyrosine Tyrosine hydroxylase

Tryptophan Tryptophan hydroxylase

Synaptic vesicles

Phenylalanine, tyrosine Tyrosine hydroxylase Dopamine-jkhydroxylase Synaptic vesicles

MAO COMT

MAO COMT

Second messengers

cAMP, Ca++, DAG, IP3, K+

cAMP, Ca+, IP3, arachadonic acid, phosphatidic acid

Synaptic vesicles MAO

5HTlA, 5HTlD 5HTlA, 5HTlC, 5HlD, 5HT2,5HT3 cAMP, Ca++, IP3, DAG, K+

cAMP = adenosine 3', 5'-cyclic phosphate, COMT = erthrocyte catecho-Osmethyltransferase, MAO = monoamine oxidase.

other NTs. For example, serotonergic neurons connect with nonserotonergic neurons. The neuron has autoreceptors at different sites that assist in self-regulation as well as postsynaptic receptors receiving signals from other neurons. The activity of that neuron is therefore dependent on regulation from other neurons as well as regulation within its own NT system. This outside regulation also works to maintain the system in balance and to respond optimally when needed. In the next section, we will describe the location of the three NT systems in the brain and the subtypes of receptors for the three NTs. Major advances have been made in the classification of receptors and in the understanding of how they function when activated. It is likely that advances in this area will lead to new pharmacological treatments and a better understanding of brain-behavior relationships. For more details regarding the synthesis and metabolism of DA, NE, and 5HT, see Cooper et al. (1986a, 1986b).

Neurochemistry and Neuroanatomy LOCATION OF NEUROTRANSMITTER SYSTEMS AND DESCRIPTION OF RECEPTORS

Location of CNS Biogenic Amine Neuronal Systems

The dopaminergic, noradrenergic, and serotonergic systems are shown schematically in Figure 1 (Bjorklund and Lindvall, 1984; Cooper et aI., 1986a). Dopamine cell bodies are present in two midbrain regions: the substantia nigra and TABLE

2.

ventral tegmental area. Noradrenergic cell bodies occur in the locus coeruleus and the lateral tegmental areas of the brain. Serotonergic cell bodies are located in the midline or raphe regions of the pons and upper brain stem. As shown in Figure 2, the axons from the cell bodies project to virtually all areas of the brain, and the three NT systems innervate many common areas of the brain. In addition, direct interaction among these three neuronal systems has been demonstrated. Although the regulation of the balance among these systems requires more study, the common areas of innervation and their direct interconnection support the hypothesis that the balance among the three NT systems may be important in the regulation and expression of behavior. Classification and Subtypes for DA, NE, and 5HT Receptors A receptor is a protein or glycoprotein in the plasma membrane whose exposed surface can specifically bind various types of chemical compounds or ligands. A receptor is classified in a variety of ways. First, a receptor is classified according to the NTs that bind to it. For example, receptors that bind the DA, NE, and 5HT with high affinity are called dopaminergic, adrenergic, and serotonergic receptors, respectively. These types of receptors have been more specifically classified into subtypes based on the differences discovered in: 1) their affinity for their particular NT and the affinity of drugs for the receptor (pharmacology), 2) the

Chemical Transmission

Initiation of transmission Release of presynaptic NT Binding of NT to postsynaptic receptors Activation of receptors Regulation of second messengers Termination of transmission Excitation of presynaptic terminal ended, therefore no further NT being released Depletion of NT and no more available for release Binding of NT to presynaptic receptors turns off the release of NT Reuptake of NT by the presynaptic terminal Metabolism by extracellular enzymes such as COMT, intracellular metabolism by MAO depleting NT available for release or rerelease

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NEUROCHEMISTRY AND CHILD AND ADOLESCENT PSYCHIATRY

Dopamine Neuronal System r=~~---- Cortex

Cingulate gyrus Caudate nucleus Septal area Hypothalamus

FIG. I. (Left) Schematic drawings of neuronal systems in coronal section of human brain. Brain structures are shown on both sides of the drawing. On the right side are listed the names of the brain structures. On the left sidethe solidlinesrepresent axonal projections from cell bodies (solid circles) to the innervated brain structures. A, Dopaminergic neuronal system. B, Adrenergic (norepinephrine) neuronal system. C, Serotonergic neuronal system.

Putamen

Nucleus accumbens Ventral tegmental area Amygdala Olfactory tubercle (not shown - ventral to this plane of section) Substantia nigra

Norepinephrine Neuronal System Cortex

~~......,

Cingulate gyrus Caudate nucleus Septal area Thalamus Hypothalamus Putamen Nucleus accumbens Substantia nigra

~~~~~~i==3L-4J- Amygdala If!'.----r-r-

Hippocampus Locus coeruleus

-

B

Cerebellum Lateral tegmental area Raphe nuclei Spinal cord

Serotonin Neuronal System r==¥""""'..-----

Cortex Cingulate gyrus Caudate nucleus Thalamus

location of the receptors (tissue distribution), 3) the gene(s) that encodes for the receptor protein (molecular biology), and 4) the intracellular activity that the receptor can activate (transduction system). The subtypes of the receptors for the three NTs and their pre- and postsynaptic location are shown in Table 1. The activation of presynaptic receptors (called autoreceptors) inhibits the release of NT, and the activation of postsynaptic receptors alters the cellular activity of postsynaptic neurons. The presence and/or density of the receptor subtypes varies in different brain regions. For example, D3 receptors are mostly present in discrete brain areas belonging to or related to the limbic system (Sokoloff et al., 1990). In addition to the receptor subtypes having different locations and different affinities for NTs and affinities for drugs, there are differences in the transduction system that the receptor subtypes activate to produce an intracellular effect.

Membrane Transducing Systems for DA, NE, and 5HT Neuronal Systems in the eNS A membrane transducing system is a cluster of proteins and lipids that usually consists of a receptor, a G protein, and a catalytic subunit (enzyme) or ion channel (Fig. 3). The receptor is embedded in the plasma membrane and is exposed on both the extracellular and intracellular sides of the plasma membrane. Specific agonists for a receptor bind to its extracellular surface with high specificity and activate the G protein that associates with a specific receptor. 0 proteins can activate (Os) or inhibit (Gi) enzymes or ion channels to which they are coupled. This physiological action results in an increase or decrease of intracellular second messengers. The level of second messengers in the cell cytoplasm or membrane dictate the biochemical activity of the cell. All of the NE, DA, and 5HT receptor types interact with G proteins. Recent studies (Oilman, 1989) have revealed that 0 proteins are made up of three protein subunits (n, ~,

Globus pallidus Putamen

~~rtlf~~~===:::tL=L:I

NORPINEPHRINE NEURONAL SYSTEM

Hypothalamus Substantia nigra Amygdala Hippocampus

~~~~_- Locus coeruleus

,L."t:.:.------

Cerebellum

Raphe nuclei / - - - - - - - - Spinal cord

J. Am. A cad. Child Adolesc. Psychiatry, 31:5, September 1992

Schematic drawing showing projections of dopaminergic, adrenergic, and serotonergic systems into common areas of the brain.

FIG. 2.

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ROGENESS ET AL. Receptor Site

Coexistence of Peptide NTs with Amine NTs We will only note, but not discuss, the recent discovery that peptide NTs coexist in nerve terminals previously thought to contain only NE, 5HT, or DA. These peptides may be coreleased with the traditional NTs on activation of a neuron. The consideration of the relative effects of the two NTs presents a whole new level of complexity in the CNS that may have significance at the physiological and behavioral level. METHODS OF MEASUREMENT OF NT FUNCTION

FIG. 3. Schematic drawing of a plasma membrane transduction system. The plasma membrane consists of a double layer of phospholipids (ball and stick models) in which are embedded various types of proteins. The receptor component of the transduction system is a protein comprised of seven membrane spanning sections with inner and outer membrane loops. This general receptor structure is identical for dopaminergic, adrenergic, and serotonergi c receptors. The regulatory G-protein, which can be inhibitory or stimulatory, consists of u, ~, and 't subun its. GDP is bound to the G-protein on the lX subunit. When an agonist binds to the receptor, GDP is replaced by GTP, and the activated lX subunit stimulates or inhibits the activity of an ion channel or enzyme associated with the particul ar receptor . Only a general structure is drawn for the functional component of the transduction system, which can be an enzyme or an ion channel. A wide variety of functions are associated with this structure.

and r) , The a subunit of Gs and Gi proteins binds either GDP (inactive form) or GTP (active form). When the agonist (NE, DA, 5HT) binds to the receptor protein on the outside of the membrane, the G protein on the inside of the membrane is activated. This activation results in the separation of the a subunit from the p and 't subunit of the G protein. The separated active a subunit either stimulates or inhibits the functional activity of the transducing system (Brown and Birnbaummer, 1988; Gilman, 1989). This activity could be an ion channel or enzyme function that regulates the levels of second messengers inside the cell. It is the interaction of second messengers in the cytosolic compartment that determines cellular neuronal function. There is additional diversity of function between cell types at the level of second messenger function . Second messengers are intracellular atoms or molecules that produce the activation or inactivation of some intracellular biochemicalor physiological activity as a function of second messenger concentration. In general, adenosine 3' ,5' -c ycl ic phosphate (cAMP) as a second messenger will cause the phosphorylation of several proteins (usually protein kinases that activate or inactivate other enzymes) within a given cell type. These kinases will vary with cell type conferring additional specificity for cAMP function . Ca" (calcium ion), also an important and well-studied second messenger, will bind to an intracellular protein called calmodulin in a ratio of 4:1. The resulting Ca* calmodulin complex will also cause the phosphorylation of several proteins, probably enzymes. Although the scope of this report does not allow a detailed discussion of second messenger induced cellular changes, second messenger action includes effects on membrane ion channels, intracellular enzymes, protein kinases, and transcription and translation processes.

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Strategies to examine for NT differences in child psychiatric disorders have included the measurement of NTs and their metabolites in urine, blood, and cerebrospinal fluid (CSF), measurement of enzymes, studies on platelets, and pharmacological probes. The use of positive emission tomography imaging is a new technique to study NT function, but its use is in its infancy in child psychiatry (Kuperman et al., 1990). Newer molecular biology techniques involving gene expression may add significantly to our knowledge of child psychiatric disorders but are beyond the scope of this review. Some of the advantages and disadvantages of the above techniques are shown in Table 3. For more details regarding the measurement of NT function in child disorders, see Rasmusson et al. (1990). INTEGRATING NEUROCHEMISTRY AND NEUROANATOMY

Increasingly, understanding hypotheses about the neurobiology of psychiatric disorders requires that the clinician take an integrated view of NT function, neurochemical pathways, and neuroanatomical structures. Increasingly, more sophisticated views of the interrelationships of the basal ganglia, cerebral cortex, and limbic system are emerging from basic science studies.deading to new thoughts on their involvement in mental illness. Recent advances in basal ganglia research indicate that the basal ganglia collect signals from a large part of the cerebral cortex, redistribute these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focus the output of these signals to particular regions of the frontal lobes and brain stem (Graybiel, 1990). The organization and function of the basal ganglia suggest it is important to learning and/or maintaining motor, behavioral, and emotional sets. Because of this role of the basal ganglia, investigators have suggested that dysfunction in the basal ganglia may be involved in the pathophysiology of schizophrenia (Carlsson and Carlsson, 1990), obsessive-compulsive disorder (Chappell et al., 1990; Modell et aI., 1989; Swedo and Rapoport, 1990), Tourette 's disorder (Chappell et al., 1990; Leckman et al., 1991), and .attention deficit hyperactivity disorder (Lou et al., 1989; Heilman et aI., 1991). Basal ganglia research indicates that there are a series of parallel cortico-striato- nigropallidal-thalarnocortical circuits (Goldman-Rakic and Selemon, 1990). It is as if each cell or functional group of cells in the cerebral cortex sends a private line through the basal ganglia and back to the cortex. Figure 4 is a simplified diagram of the path of these circuits. J. Am.Acad. ChildAdolesc.Psychiatry,31.'5,September1992

NEUROCHEMISTRY AND CHILD AND ADOLESCENT PSYCHIATRY TABLE 3. Neurochemical Measures

A. Body fluids The majority of neurochemical studies in child psychiatry have measured NTS and their metabolites in cerebrospinal fluid (CSF), blood, or urine. Some advantages and disadvantages of each are outlined below. The metabolites commonly measured for norepinephrine are 3-methoxy-4-hydroxyphenylglycol (MHPG), vanillymandelic acid (VMA), and normetanephrine (NMET); for dopamine are homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC); and 5-hydroxyindoleacetic acid (5-HIAA) for serotonin. Advantages Disadvantages CSF

More directly measures brain metabolism of NTs

Plasma

(a) Relatively noninvasive (b) Can obtain repeated samples (c) Significant percentage of HVA and MHPG are from CNS metabolism (a) Noninvasive (b) Large quantities enable one to measure all the metabolites and look at relationships among NTs and metabolites (c) Can obtain quantitative measure of production of NTs and metabolites in 24-hour production

Urine

1. Cannot differentiate from what functional site metabolites are produced 2. Invasive 3. Measures at only one point in time. Hard to do repeated spinal taps 4. Exchange takes place between CSF and plasma for some metabolites such as MHPG (a) Reflects more peripheral than CNS metabolism

(a) More reflective of peripheral metabolism (b) More difficult to collect accurate and complete samples

B. Enzymes Enzymes such as D~H, COMT, and MAO can be measured from blood samples. Advantages are that samples are easily obtainable and the enzyme activities are genetically determined and tend to be relatively constant over time. A disadvantage is that the activity of the enzyme may bear no direct relationship to the functional activity of the NTs. C. Platelet as a model of the synapse The platelet functionally resembles the serotonin nerve ending. It has therefore been used for a variety of studies including NT content, NT uptake, NT receptors, and NT transducing systems. Advantages Disadvantages 1. Accessible 2. Able to measure a variety of functions that are necessary for synaptic function

1. Technically difficult 2. May not be a direct relationship between platelet function and synaptic function in the CNS

D. Probes Certain drugs stimulate receptors for a specific NT. For example, clonidine stimulates the ~ receptor. By using these agents and then evaluating functional or chemical responses to the agent, one may learn how the particular NT system is functional in an individual. Disadvantages are that it may be a relatively invasive procedure in children and that the probes may affect more than one system making the results difficult to interpret. E. Brain imaging Brain imaging will allow for evaluation of specific neurotransmitter systems in the CNS. This use of these procedures have recently been reviewed in the Journal of the American Academy of Child and Adolescent Psychiatry (Kuperman et al., 1990).

The circuits from each cortical area appear to consist of both a direct circuit and an indirect circuit (Alexander and Crutcher, 1990). Increased output through the direct circuit results in increased excitation of cortical neurons, whereas increased output through the indirect circuit results in a decrease in excitation of cortical neurons. The direct and indirect pathways therefore have opposite effects. The function of the circuits is best understood in terms of motor functions. The basal ganglia appear to participate in enabling particular movements and controlling sequencing of these movements, rather than directly causing them to occur. Disinhibition of the basal ganglia alone is not sufficient to trigger a coordinated movement. A command signal from other sources is also necessary (Chevalier and Deniau, 1990). J. Am. Acad. Child Adolesc. Psychiatry, 31:5, September 1992

DA neurons reside in the substantia nigra compacta, which receives input from the striatum. The DA neurons of the substantia nigra compacta terminate primarily on neurons in the dorsal striatum. The function of the DA input to the striatum may be to reinforce any cortically initiated activation of a particular circuit, perhaps by having contrasting effects on the direct and indirect circuit (Alexander and Crutcher, 1990). Therefore, in Parkinson's disease, where DA neurons are lost in the substania nigra compacta and DA input to the striatum is decreased, the basal ganglia would be less responsive in enabling particular movements and their sequencing. The commands for action would be sent to basal ganglia, but the response of the basal ganglia circuits would be slowed, and the motor action would be initiated more slowly with poorer control over sequencing.

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The response to signals to stop the motor action would also be slowed. One of the characteristics of Parkinsonism is difficulty in initiating movements and once the movement is started, stopping it. The command center gives the orders, but because of the DA deficiency, the responses to the orders are overly slow. By analogy, one could hypothesize that excessive nigrostriatal DA input or tone would lead to the basal ganglia circuits being overly responsive and responding too quickly to commands or perhaps even responding spontaneously. Such a condition could occur in Tourette's disorder resulting in tics and vocalizations. Even if the basal ganglia disinhibition in Tourette's was not due to excessive DA tone, blocking of DA input to the striatum by neuroleptics would decrease the responsiveness of the basal ganglia circuits and have the beneficial effect of decreasing the tics and vocalizations. The basal ganglia participate in a number of functions, including cognitive and limbic processes. There are cognitive (Brown and Marsden, 1990) and affective changes in Parkinsonism (Wilner, 1983a), and these changes could be due, in part, to the decreased dopaminergic input to the cognitive and limbic portion of the striatum. Similarly, some of the obsessive compulsive symptoms in the form of obsessive-compulsive disorder associated with Tourette's disorder could relate to an increased dopaminergic tone in cognitive striatal circuits with a resultant tendency to repetitive, intrusive thoughts and behaviors. The limbic or ventral striatum (nucleus accumbens and BASAL GANGLIA CIRCUITS Cerebral Cortex

Excitation

Striatum DorsalStriatum: Putamen Caudatenucleus VentralStriatum:NucleusAccumbens OlfactoryTubercle ............. Inhibition

Substantia Globus Nigra Pallidus Compacta Externa dOpamine ) ( cell bodies L.-~_---J

Substantia Globus Nigra Pallidus Reticularis Interna L.-....... _--:-_r-..J

Excitation Release

i;~;;; Inhibition .'.

Subthalamic Nuclei

-

• ••• •••.• p2:.:: .....• ..

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 . . . . . . . . . . "

Direct pamway- excitestargetedcortical neurons

........'" Indirectpathway- inhibitstargeted corticalneurons

FIG. 4. Schematic drawing of direct and indirect cortico-striatonigro/pallidal-thalamocortical circuits. Each functional group of cortical cells appears to send private lines (direct and indirect circuits) through the basal ganglia to the thalamus and back to the cortex.

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olfactory tubercle) receives input from the limbic cortex, the amygdala and hippocampus, which are structures critical in learning, memory, and affective behavior. The nucleus accumbens projects to the globus pallidus ventralis and to the substantia nigra compacta. The projections to the substantia nigra compacta influence DA input to the sensorimotor striatum (Smith and Bolan, 1991). Thus activation of the nucleus accumbens by the limbic cortex results in disinhibition of the limbic-striatal-pallidal-thalamos-corticalloop as well as influencing dopaminergic input to the sensorimotor striatum from the substantia nigra compacta. DA input to the nucleus accumbens is from a group of cells in the mesencephalon, termed the ventral tegmental area. These cells project to the nucleus accumbens in a manner analogous to the way substantia nigra compacta neurons project to the sensorimotor striatum. DA input to the nucleus accumbens may therefore "tune" the circuits leading from the nucleus accumbens, influencing sensorimotor responses as well as affective and cognitive responses. Together with the endogenous opiates, the ventral tegmental area to the nucleus accumbens dopamine pathway may be critical in the experience of reward (Petit et aI., 1984; Wise, 1983; Wise and Rompre, 1989; Zito et aI., 1985). Cloninger (1987) hypothesized that individuals with a highly active dopaminergic system (possibly on a genetic basis) were more likely to seek novelty and reward and would be predisposed to abuse alcohol and other drugs. Such individuals might derive a greater sense of pleasure from commonly abused drugs (due to more active "reward pathways") and would be more vulnerable to addiction. Another brain system important in the modulation of affective behavior is the Papez circuit. This circuit begins in the limbic cortex (the cingulate gyrus) and projects to the entorhinal cortex (a part of the temporal lobe). The hippocampal formation forms the next part. From here the circuit flows to the mamillary bodies, on to the thalamus, and back to the limbic cortex. Neuronal activity through the circuit is modulated by NE neurons from the locus coerulus and by 5HT neurons from the raphe nucleus. Gray (1982) describes the input to the entorhinal area. Essentially, there is convergent input from all major areas of the neo and limbic cortex, such that the hippocampus must have access to nearly all on going stimuli, albeit in a highly processed form. Furthermore, the locus coerulus and raphe constantly modulate the activity of the septohippocampal system. In live animals, correlations can be found between the rhythm of the hippocampal cells and certain types of behavior (for reviews, see Gray, 1982; O'Keefe and Nadel, 1978). Thus the hippocampus is well situated to examine the current state of the organism's world, and send information back to the limbic cortex, septal region and hypothalamus to guide behavior. The hypothalamus, as the "head ganglion" of the autonomic nervous system, can control the output of the autonomic nervous system in "fight or flight" situations. The septohippocampal system outlined above plays an essential role in Gray's (1982) theory of anxiety. In general, DA, NE, and 5HT appear to have modulatory J. Am.Acad. ChildAdolesc.Psychiatry, 31:5, September1992

NEUROCHEMISTRY AND CHILD AND ADOLESCENT PSYCHIATRY

effects on the above systems: "tuning" the systems, and/or increasing or decreasing the responsiveness of the system. The anatomy of the three NT systems is consistent with such a tuning role with each of the biogenic amines sending projections to widespread areas of the brain from only a few centers (Figs. I and 2). An important function of these three biogenic amines may therefore be to assist the organism in keeping different brain systems in proper tune to meet the changing demands of the environment and learn more effectively from the environment. In the next sections we will discuss further how this interaction or tuning of the three biogenic amine systems may playa part in child psychiatric disorders followed by a review of some of the neurochemical studies in child psychiatry. It should be borne in mind, however, that while these theories have great heuristic value, it is very difficult to test these hypotheses in humans, and at present there are no direct clinical applications of this work. Behavioral Systems and Child Psychiatric Disorders BEHAVIORAL SYSTEMS

NE, DA, and 5HT systems appear to be important in the interaction and regulation of an individual's behavior with the external environment (Antelman and Caggiula, 1977; Depue and Spoont, 1986). DA appears to be the NT most involved in the expression of active behavioral patterns that include motor activity, aggressive behavior, and sexual behavior. NE and 5HT appear to be involved in regulating the DA dependent behavior. NE, with support from 5HT appears important in attending to and assessing the environment. These systems have been defined primarily in nonhumans, but appear applicable to humans as well. In the descriptions that follow, we will take some liberty by giving hypothetical human examples that will make it easier to see how these system may affect learning and behavior in humans and may therefore apply to child psychiatry. Based on the function of these systems, we will then make hypotheses about dysregulation in these systems and resulting behavior patterns. Gray (1982; 1987) has described a behavioral facilitatory system (BFS) and a behavioral inhibitory system (BIS). Quay (1988a, b) has elaborated on Gray's work and hypothesized how these systems may relate to child psychiatric disorders. The BFS is a generalized behavioral system that functions to mobilize behavior so that active engagement with the environment occurs. Examples of such behaviors include extraversion, sexual behavior, and aggressive behavior. The components of the BFS are thought to be integrated in the mesolimbic dopaminergic system (Depue and Spoont, 1986; Gray, 1982). The BFS is activated primarily by rewarding stimuli or by aversive stimuli when escape or avoidance is possible. For example, a child sees a candy bar in a store. The BFS is stimulated by this environmental stimuli and sets off the behavioral sequence to get the candy bar and eat it. The BFS is action with no restraint. The restraint is provided externally by the mother who prevents the action. Escape/avoidance is also considered rewarding. The boy, after taking candy, sees the store clerk coming and escapes/ J. Am. Acad. Child Adolesc. Psychiatry, 3J:5, September J992

avoids the aversive consequences by running from the store and/or lying about what he did. The BFS responds to signals from the environment with action. If its action is blocked (prevention from taking the candy or running away), frustration occurs, and an aggressive response may occur that may also be dependent on a dopaminergic system. Without an internal system to provide restraint, the individual would be completely dependent on the external environment for restraint. The BIS is· the internal system to provide restraint. The BIS acts as a comparator and an inhibitor of behavior (Gray, 1982; 1987; Depue and Spoont, 1986). The BIS continuously compares actual environmental circumstances with concepts of expected outcome of behavior. When mismatches occur, the BIS stops behavior by inhibiting the BFS. The neurobiological foundation of the BIS appears to be the septohippocampal system. The regulation of the septohippocampal system appears to be noradrenergic with additional regulation from serotonergic projections from the median raphe. The conditions to which the BIS responds are nonreward, punishment, and uncertainty. Affectively, frustration may be associated with nonreward, and fear and/ or anxiety with punishment and uncertainty. Returning to the example of the boy in the candy store, the BFS would be activated by the reward of candy. The BIS would then evaluate the situation. If the evaluation suggested that punishment would occur, then the BIS would be activated and the behavior inhibited. The BFS is inhibited internally by the BIS rather than relying on external restraint to control the BFS. The relative strengths of the BFS (dopaminergic system) and BIS (noradrenergic/serotonergic systems) would theoretically influence behavior at a given point in time. For example, an individual with a strong BFS and a weak BIS would be overly responsive to rewarding stimuli in his environment and tend to ignore the negative consequences that might occur when he sought the reward. Because the individual would be "messing up" frequently, even when he did not intend to, there would be a strong tendency for him to be demoralized and have a poor self-esteem. In addition, the relative strengths of the system would also influence the development of behavioral patterns in an individual over time through the influence on learning in the individual. For example, a child with a strong BIS would show good attention to and discriminating ability to the environment. When punished for stealing he would respond to the punishment with fear/anxiety. The next time he would respond with fear and anxiety to signals of punishment (the thought of stealing) and the stealing behavior would be inhibited. Eventually, the thought of stealing would not even occur, and the child could be trusted without supervision. The child would quickly internalize societal rules and would do well with minimal supervision. In contrast, a child with a strong BFS relative to his BIS, would internalize poorly and be much more dependent on environmental controls to maintain socially appropriate behavior. In addition, since this child is conditioning poorly to signals of punishment, he would have less insight into the reasons for his being punished and be more likely to blame others for his problems.

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ROGENESS ET AL.

NE (Antelman and Caggiula, 1977; Plaznik and Kostowski, 1983) and 5HT (Coccaro, 1989) have been shown to inhibit, and DA to facilitate, irritable aggression. Serotonergic mechanisms appear stronger in inhibiting irritable, aggressive behavior than do noradrenergic systems, and there is extensive animal and human literature showing 5HT' s role in inhibiting aggressive behavior (Coccaro, 1989). Some of the inhibition of aggressive behavior by 5HT appears mediated from the median raphe through the BIS (Depue and Spoont, 1986). The serotonergic projections from the dorsal raphe to the amygdala appear to playa larger role in inhibiting aggression (Pucilowski and Kostowski, 1983) than the projections from the median raphe to the septohippocampus. Antelman and Caggiula (1977) have elegantly described NE-DA interactions. Among their conclusions are that NE regulates DA dependent behaviors and that when both NE and DA are depressed equally, one may not see the changes in behavior that occur when either one or the other is depressed. The implications of this later point are that it may be the balance between the regulatory systems, i.e., BFS and BIS, rather than the absolute strength of the systems that determines normal behavior. If the systems are in balance, the intensity of the normal behavior may be different, but it might not deviate from the norm. Dysfunctional behavior may occur when the regulatory systems are out of balance. In this paper, the regulatory systems of interest are the dopaminergic (BFS), noradrenergic (BIS), and serotonergic (BIS, dorsal raphe-amygdala). The development of and balance among these three systems may be influenced by environmental factors as well as being genetically determined. Environmental factors include psychosocial factors as well as physical factors. The three biogenic amine systems continue their active development after birth, and developmental factors may have permanent effects on these systems. DEVELOPMENTAL FACTORS

Developmental changes in the dopaminergic and serotonergic systems are reflected in a decline of CSF HVA and CSF 5HIAA with age (Gillberg and Svennerholm, 1987; Kruesi et aI., 1990; Langlais et aI., 1985; Seifert et aI., 1980; Shaywitz et aI., 1980; Silverstein et aI., 1985). These studies do not show that CSF 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of NE, changes with age after the first 8 or 9 months of age, suggesting that the relative activity of the noradrenergic system in relationship to the dopaminergic and serotonergic systems may be increasing with age, perhaps increasing internal restraint. Receptor density also changes with age. Seeman et aI. (1987) quantified binding to Dl and D2 receptors in human postmortem brains from birth to 104 years of age. The density of both receptors rose sharply between birth and 2 years of age and then dropped sharply from age 3 to age 10. From age 10 through adulthood, there was a slow but steady decline. The ratio between Dl and D2 receptors also changed with age. The ongoing development of the NT systems after birth suggest that factors that alter their development may affect

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the behavior of the subject and that the affect on behavior may be different given the different developmental age of the subject. A well known natural experiment that illustrates this is Von Economo's encephalitis, which affects the DA system and produces Parkinsonism in adults and hyperactivity in children (Grinker and Saks, 1966). Shaywitz et aI. (1976a) repeated this natural experiment by depleting DA in infant rats. The young rats showed an increase in activity (hyperactivity) that was responsive to amphetamine (Shaywitz et aI., 1976b). Primate studies suggest that psychosocial factors can affect the development of NT systems and that these changes may be permanent and may affect behavior in adulthood. Kraemer et aI. (1989) made repeated measures of CSF amines on mother-deprived and mother-reared infants. Mother-deprived infants had lower levels of CSF NE than mother-reared infants. The intercorrelations between measures of 5HT, NE, and DA also differed suggesting that either the balance between these systems was altered or that one or more of these systems had become less stable. In an earlier study, Kramer et aI. (1984) (Kraemer et aI., 1984) had shown that adult monkeys who had been maternally deprived were hypersensitive to n-amphetamine, suggesting that the psychosocially induced changes during early development had caused permanent changes in the NT systems affected by D-amphetamine. CSF NE was significantly higher in mother-deprived infants following n-amphetamine administration suggesting that the NE system was the one that had been affected most by early deprivation. HYPOTHETICAL RELATIONSHIPS AMONG BIOGENIC AMINE SYSTEMS AND BEHAVIOR

Gray (1987) has hypothesized that the relative strengths of the BFS and BIS may be important in the development of personality characteristics, such as extraversion and intraversion, as well as deviant characteristics such as antisocial disorder and anxiety disorders. Cloninger (1987) has hypothesized that excessive mesolimbic dopaminergic activity may make an individual reward driven and subject to the development of addictions. Based on the hypothesized role of NE, DA, and 5HT in the development of the above behaviors and the likelihood that the balance between the three systems is important, one can make hypotheses regarding possible behaviors that could be associated with high or low functioning in each of the NT systems (Table 4), and symptom groups that might occur with different balances among the three systems (Table 5). The information in Tables 4 and 5 is speculative and is an oversimplification based on current information but is helpful in conceptualizing possible biochemical-behavioral relationships. If relationships between behavior and the three systems hold as shown in Table 5, it has important implications for design of biochemical studies and the interpretation of results. For example, if subjects whose three systems are in balance all fall into the normal behavioral spectrum, a control group of subjects will have a full range of NT measures and frequently not differ from a patient sample. Measuring only one NT system might give misleading results, because the functional effect of that NT system being high or low J.Am.Acad.ChildAdolesc. Psychiatry, 31:5, September1992

NEUROCHEMISTRY AND CHILD AND ADOLESCENT PSYCHIATRY TABLE 4.

Possible Characteristics Associated with Level of NT System Functional Activity

High

Low

Dopamine

Increased motor activity, aggressive, extroverted, reward driven

Decreased motor activity, nonaggressive, low interest in others, poor motivation

Norepinephrine

Good concentration and selective attention, conditions easily, internalizes values, easily becomes anxious, overly inhibited, introverted Good impulse control, low aggression

Inattentive, conditions poorly, internalizes poorly, low anxiety, under inhibited

Serotonin

would be dependent, in part, on the functional activity of another NT system. Because obtaining measures on a single NT system may give misleading results, the most effective strategy for identifying relationships between NT systems and behavior would be to obtain measures of all three systems in an individual. Also, one may wish to select comparison groups that are theoretically quite different biologically. Using "normal" controls as a comparison group may be misleading since a normal control group could have a full range of values, but be in balance. Two groups that would lead to a best comparison might be a conduct disorder (CD) group without anxiety or depression versus an anxiety/depressed group without CD. Based on the theoretical function and relationship between the three NT systems, one can make testable hypotheses about behavior patterns in children based both on the strength of one of these systems and on the balance between the three systems. The child psychiatric disorders that have been studied most are infantile autism, attention deficit hyperactivity disorder (ADHD), CD, major depressive disorder, and Tourette's disorder. All of these disorders, except for infantile autism, could be seen as disorders secondary to dysregulation or imbalance of the three NT systems. In the next section, we will review neurochemical studies in these four disorders to see if the data provide any support for the above hypotheses. Neurochel11i5al Studies in Child Psychiatric Disorders MAJOR DEPRESSION

Major depression, anxiety disorder, and behavioral inhibition may be associated with high NE and 5HT function and normal to low DA function . The dexamethasone suppression test is positive more freTABLE

Poor impulse control, high aggression, increased motor activity

quently in children and adolescents with major depressive disorder than in children and adolescents with other psychiatric diagnoses (Casat et al., 1989). The increased hypothalamic-pituitary-adrenal axis activity, suggested by the nonsuppression of serum cortisol, may be related to either decreased noradrenergic activity (Sachar et al ., 1981; . Schlesser et al., 1980) or increased noradrenergic activity (Jimerson et al., 1983; Rosenbaum et al., 1983; Rubin et al., 1985). The growth hormone response to stimulation by several different biological probes has been shown to be blunted in major depressive disorder in children (Jensen and Garfinkel, 1990; Puig-Antich et al., 1984a; 1984b). Jensen and Garfinkel (1990) suggest that this blunted response may be due to dysregulation in postsynaptic alpha adrenergic receptors and in postsynaptic DA receptor sites. Twenty-four hour urine MHPG, a metabolite of NE, was lower in hospitalized depressed children than in healthy outpatient controls; however, children on an orthopedic unit had significantly lower levels of MHPG than the depressed children. There were no differences in NE or vanillyrnandeIic acid (VMA), another metabolite of NE (McKnew and Cytryn, 1979). Khan (1987) found no differences in MHPG between depressed and control adolescents. De Villiers et aI. (1989) measured plasma NE and MHPG in depressed adolescents and found no difference in comparison with healthy adolescents. These studies suggest no change in the excretion of NE in depression. Carstens et al. (1988) measured