Dopaminergic schizophrenia

mechanisfl*in

the pathogenesis

of

MENEK GOLDSTEIN2 AND ARIEL 1.DEUTCHt Department of Psychiatr#{231} New York Uni4sity School of Medicine, New York, New York 10016, USA; and tDepi of Psychiatry, Yale UnivereitySchool of Medicine, New Haven, Connecticut 06510, USA, and tDepartment of Veterans
Affairs Medical

(rter,

West Haven,

Connecticut

06516, USA

ABSTRACT The dopamine hypothesis of schizophrenia has been the dominant theoretical construction guiding research and treatment of the schizophrenic disorders over the past generation. This hypothesis, in its simplest guise, posits the presence of a functional alteration in central dopaminergic systems in the brains of schizophrenic patients. Recent findings have resulted in a greater understanding of the complexity of the central dopaminergic systems and have led to revisions of the hypothesis of a simple functional hyperactivity of central dopaminergic systems. These recent data suggest that there may be regionally restricted changes in the function of the mesotelencephalic dopamine system, and that these changes may be in opposite directions. Such changes may be associated with dysfunctions of interactions between distinct dopaminergic terminal field regions, and may be subserved by functional derangements in other transmitter systems or reflect regionally restricted changes in expression or function of distinct dopamine receptors or catecholamine synthetic enzymes. A recent FASEB symposium reviewed new advances in molecular biology, biochemistry, pharmacology, anatomy, and systems neuroscience as they relate to schizophrenia, and discussed the implications of these data for guiding future research and treatment strategies.Goldstein, M.; Deutch, A. Y. Dopaminergic mechanisms in the pathogenesis of schizophrenia. FASEBJ. 6: 2413-2421; 1992. Key Words: dopamine . antipsychotic drugs . cholecystokinin cortex excitatory amino acids neurotensin . dopamine receptors

ogy, biochemistry, pharmacology, anatomy, neuroscience have led to a greater appreciation plexity of the central dopaminergic systems, tions with other defined transmitter systems and their role in complex cognitive processes.

and systems of the comtheir interacin the brain,

DA RECEPTORS

THE

DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA, in perhaps its most simple form, posits the existence of a functional alteration in central dopaminergic systems in the brain of schizophrenic patients. This hypothesis is based primarily on pharmacological evidence. All the known clinically effective antipsychotic drugs (as demonstrated in double-blind, placebo-controlled studies) block dopamine D2 receptors. Although actions of these agents on other transmitter receptors may augment or modify therapeutic responsiveness, the fact that all antipsychotic drugs (APD5)3 are D2 antagonists but share no other common action on any known receptor suggests that there is a functional derangement (or derangements) of central dopammne (DA) systems in schizophrenia. This conclusion is buttressed by the fact that chronic administration of indirect DA agonists, such as amphetamine, may result in a psychotic state that in many aspects resembles schizophrenia. Accordingly, there has been the targeting of both basic and clinical science studies of schizophrenia on central dopaminergic systems. Advances in molecular biol-

If the dopamine hypothesis of schizophrenia is correct, it should be possible to uncover some change in 1) DA content or turnover, 2) DA neuronal responsiveness to perturbation, or 3) the density or affinity of DA receptor sites in postmortem brain samples from schizophrenic patients. This task has frequently been disappointing, marked by several instances of promising findings languishing after attempts at independent verification have failed. This is perhaps not surprising: the problems encountered in working with postmortem samples (such as agonal state, postmortem interval, and regional dissection differences), as well as the problems inherent in diagnosis, heterogeneity of the schizophrenias, and the presence or history of APD treatment, are well known. Nonetheless, the lack of consistent changes in concentrations of DA or its metabolites has led some investigators to suggest that the defect in schizophrenia is not of DA systems, and others to propose that the alteration in central DA systems is more subtle than a simple change in levels of DA or its metabolites. Some reports have suggested that DA receptor density may be elevated in schizophrenia (see ref 1). Changes in the number of D2 receptors are perhaps the most consistent alterations reported from postmortem tissue, although there are dissenting votes as well. It is possible that changes in receptor density are not constant throughout the course of the disease (1) or that the changes are more subtle than simple differences

1From the symposium Dopaminergic Involvement in Schizophrenia and Other Mental Disorders presented by the American Society for Pharmacology and Experimental Therapeutics at the 74th Annual Meeting of the Federation of American Societies for Experimental Biology, April 2, 1990, Washington, D.C. Participants included A. Barnett, B. S. Bunney, A. Carlsson, A. Y. Deutch, K. Fuxe, M. Goldstein, T Hokfelt, 5. -0. Ogren, P. Seeman, C. A. Tamminga, and D. R. Weinberger. Organized by M. Goldstein and A. Y. Deutch. 2To whom correspondence should be addressed at: Neurochemistry Laboratories, Room H544, NYU Medical Center, 560 First Ave., New York, NY 10016, USA. 3Abbreviations: APDs, antipsychotic drugs; PET, positron emission tomography; CCK, cholecystokinin; NT, neurotensin; EAA, excitatory amino acid; PCP, phencyclidine; LCGU, local cerebral glucose utilization; PFC, prefrontal cortex; EPS, extrapyramidal side effects; DA, dopamine.

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FASEB

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in receptor number. Among studies supporting the latter view was the finding that there is a bimodal distribution of D2 receptor density, and that only in one of these modes can a change in the density of D2 receptors be discerned (1). Although one can exclude effects due to APD pharmacotherapy through statistical means, in the absence of tissue from patients never treated with APDs it is difficult to establish conclusively the degree to which an increase in receptor number is iatrogenic or reflects the schizophrenic process. An alternative strategy to the problem of defining changes in receptor density or affinity has been to use in vivo imaging techniques. Recent attempts have used positron emission tomography (PET) to assess the possibility of changes in the number of striatal D2 receptors in schizophrenic patients not treated with APDs. Unfortunately, these imaging studies have yielded conflicting results (2, 3); this may be attributable to the different ligands used in the studies or to differences in patient populations. Difficulties in clearly establishing a change in central DA function in schizophrenic subjects have led to the hope that an examination of other parameters of DA function, particularly those made possible by advances in molecular biology, will enable one to determine if there are indeed changes in central nervous system (CNS) DA systems in schizophrenic psychoses. Molecular biology of DA receptors

Molecular biological strategies have resulted in the cloning of a number of DA receptor genes. The DA receptors are G proteincoupled receptors with seven transmembrane-spanning domains. The sequence homology between the conserved portions of the protein, particularly the membrane-spanning regions, opened the possibility of using probes for other G protein family receptors to screen libraries for DA receptors. This strategy was rewarded with the initial cloning of a D2 receptor eDNA (4); subsequent studies revealed that this gene was subject to alternative splicing, leading to two D2 receptors with differences in the third cytoplasmic loop at or near the G protein-binding domain. More recent studies have led to cloning of the putative D3 receptor, which in terms of binding characteristics appears to be a D2 isoform. Paradoxically, binding of ligands to this receptor is not changed in the presence of guanine nucleotides, suggesting that the protein is not G protein coupled; further work will be required to establish the biochemistry of this receptor and to determine whether the D3 protein represents a functional receptor. Finally, over the past year still another DA receptor, the pharmacology of which generally conforms to a D2-type receptor, has been cloned; this has been designated the D4 receptor. In addition, another D2 type receptor has been cloned, which differs from the others by virtue of gating a calcium current. The nomenclature for the recently cloned DA receptors is still a matter of debate. Extended discussion will no doubt be required before a consensus regarding the defining characteristics (for example, molecular vs. pharmacological) will be reached. On the basis of the pharmacology of the expressed protein, we will refer to all of the above-mentioned receptors as D2 isoforms, and specifically designate the alternative splice products of the original D2 receptor clone as D2A and D28, and the more recently cloned members as D3 and D4 (see ref 5). Although these receptors can be broadly classified as D2 isoforms on the basis of general pharmacological characteristics, distribution of the mRNAs for the various forms differ somewhat, leaving open the possibility that differences in the action of APDs may, in part, be attributable
to the heterogeneous distribution of specific

the brain. Designation of these receptors as falling broadly a D2 class is meant simply to serve as a convenient heuristic for the moment; the molecular biology of DA receptors is evolving at such a rapid pace-and the corresponding generation of subtype-specific ligands is lagging so far behind - that a plateau must be reached before some consensus can be achieved. D1 receptors have also recently been cloned (see ref 5). The D1 receptors cloned so far resemble other receors that result in adenyl cyclase stimulation, with a relativ 1y short third cytoplasmic loop. The first D1 receptor to be cloned has now been joined by two more D1 receptors. One of these closely resembles the original D1; the other D1 receptor cloned has a significantly higher affinity for DA. In addition, still another D1 receptor, with slightly different pharmacological characteristics, has been cloned; this receptor has been designated D5. It is likely that other D1 receptors (for example, a striatal D1 receptor coupled to phospholipase C), as well as additional D2 receptors, will be cloned in the future. This is clearly supported by observations tht certain DA receptors in the brain, such as the D2 receptor in the prefrontal cortex of the rat, have pharmacological profiles that differ from those of the DA receptors that have now been cloned (see ref 6). Rapid advances in the cloning of DA receptors and the availability of specific probes with which to assess DA receptor gene expression have raised the hope that it may be possible to define specific alterations in the gene expression of various DA receptors in postmortem tissue and to characterize a linkage with the D2 receptor region in extended families of schizophrenic patients. Current studies suggest no linkage between the D2 DA receptor and schizophrenia (7). However, more extensive investigations with specific DA receptor probes for tightly defined regions of the chromosome may prove instructive. It should be realized that a description of a change in gene expression leaves other equally important questions to be resolved: Is gene transcription specifically altered? Is the mRNA translated appropriately? Is posttranslational processing altered? What is the normal role of these DA receptors in behavior and in psychopathological conditions? Fortunately, the investigation of these questions can be guided by recent developments of the biochemistry and pharmacology of central DA neurons.
within

Biochemistry

and

pharmacology

of DA receptors

The deduced amino acid sequence of the cloned DA receptors allows the prediction of the size of the expressed protein. Results of biochemical examinations of partially purified receptor protein have deviated from these predictions to a certain degree. Differences between the predicted and actual masses of the receptors are thought to be attributable to posttranslational modifications of the protein, including glycosylation. The D2 receptor has been examined by photoaffinity labeling of receptor preparations with [25]N3-NAPS, followed by SDS gel electrophoresis and treatment with endo- and exoglycosidases (8). Such studies have revealed that the D2 receptor consists of a protein core with an estimated molecular mass of approximately 44 kDa, consistent with the value derived from the amino acid sequence of the cloned D2 receptor (4). protein

Other glycosylated species are also present and show several bands on SDS gels, with masses ranging from 34- to
(9). The 34-kDa photolabeled band is an N-linked

140 kDa yields

glycoprotein,
a protein

which
with

upon

digestion

with

D2 isoforms in

an apparent

molecular

glycopeptidase F mass of 23 kDa.

2414

Vol. 6

April

1992

The FASEB Journal

GOLDSTEIN

AND

DEUTCH

These studies suggest that the D2 receptor may consist of two common binding units of approximately 44 and 23 kDa. However, Goldstein and colleagues (10) noted that [25]N3NAPS photoaffinity labeling of the purified D2 receptor obtained from the prolactin-secreting 7315a adenohypophyseal tumor, or from the tumor-derived cell line MMQ, labels a major protein of 32-34 kDa. Northern blot analysis of the D2 receptor mRNA isolated from the solid tumor and MMQ cells reveals mRNA of the same size as the rat striatum (J. Y. Lew and M. Goldstein, unpublished results). Although there are difficulties in resolving on gels different mRNA species of similar size, these data suggest that the D2 binding units of 34-140 kDa may be derived from the same gene, and that differences in the mass of these receptor proteins are due to posttranslational modifications. The molecular relation between these units, as well as their role in mediating neuronal events, has not yet been established. Studies of the mechanisms through which the DA receptors are regulated, and examination of the mechanisms through which DA receptors in turn regulate DA synthesis, may offer important clues into treatment strategies for schizophrenia. Several recent developments have furthered our understanding of the regulation of DA receptors. DA receptors, by virtue of changes in receptor density or affinity, become more or less responsive (supersensitivity and desensitization) to stimulation after changes in exposure to receptor ligands. The DA hypothesis of schizophrenia suggests that DA receptors might be supersensitive. Although the development of denervation and drug-induced supersensitivity of DA receptors has been relatively well characterized, less well understood are the means through which desensitization is manifested. These processes have been the focus of recent investigations of and 13-adrenergic receptors, which have demonstrated that desensitization involves phosphorylation of the receptor (11). Phosphorylation of the DA receptors has not been extensively investigated. The use of synthetic peptides to specific amino acid sequences of the D2 receptor has allowed initial studies of the phosphorylation of DA receptors. Lee and colleagues (12) have recently generated peptides corresponding to amino acids 221-235 (designated D2-3) and 332-343 (D2-5); these peptides are phosphorylated in the presence of the catalytic subunit of protein kinase A. The Km of the peptides is approximately 132 and 200 jM (D2-3 and D2-5, respectively), with Vmax of 0.28 and 0.98 tM . min . mg (12). As the Km values for restricted peptide sequences are usually higher than those for the haloprotein, it is conceivable that the Km for phosphorylation of the D2 receptor by protein kinase A is in the range of the physiological concentration of the receptor protein. Several other peptides corresponding to other segments of the D2 receptor have also been tested as substrates for kinase-induced phosphorylation. A peptide corresponding to amino acids 144-152 has proved to be a substrate for protein kinase C, whereas another peptide sequence (AA 220-233) is a substrate for both protein kinases A and C (J. Grebb, P. Greengard, and M. Goldstein, unpublished data). Phosphorylation of solubilized and semi-purified D2 receptor (13) has also been examined. Several phosphoproteins can be seen after protein kinase A-induced phosphorylation of the receptor; one of these corresponds to the molecular mass (92-94 kDa) of a D2 binding unit (12). Other recent reports also examined the regulation of purified D2 receptor, and indicate that protein A-induced phosphorylation of the D2 protein reduces affinity of the receptor for DA agonists but not antagonists (14). Studies of the mechanisms through which DA receptors are regulated have predominantly fo-

cused on the D2 receptor; additional attention directed toward elucidation of regulatory other DA receptor isoforms in the future. Interactions There
the

will have to be mechanisms of

between

DA receptor

subtypes

remarkable growth in our understanding of of interactions between DA receptor subtypes. Barnett and associates (15) have reviewed pharmacological and behavioral studies detailing the function of Dl receptors. In many cases, D1 receptor stimulation potentiates the expression of D2 receptor function (16). Such interactions may have important implications for the treatment of schizophrenia with antipsychotic drugs. Accordingly, considerable attention has been devoted to elucidating the mechanisms through which D2 and D1 receptor subtypes may interact. The ability to localize the mRNAs for the various DA receptor subtypes has revealed that interactions between D1 and D2 isoforms may occur in at least two distinct ways: one involving interactions between different neurons, the other via D2-D1 interactions operative in the same cell. In situ hybridization studies have revealed D2 mRNA in approximately half of the striatal medium spiny neurons (17); the D1 mRNA has similarly been localized to approximately half of the striatal medium spiny neurons (18). Interactions between D2 and D1 receptors may be understood in terms of the presence of these two receptor types in different striatal neurons. The D2 receptor appears to be localized to the striatal neurons expression GABA and enkephalin (i.e., the striatopallidal neurons); the D1 receptor is predominantly localized to striatal projection neurons containing GABA and substance P (striatonigral neurons) (19). In addition to the separate localization of DA receptor genes to different striatal cells, both D2 and D1 mRNAs are present in the same neuron in a smaller percentage of striatal cells (20). Little is known of the precise neuronal localization of other DA receptors that have been cloned, including the putative D3 receptor (which has been reported to be present in the ventral but not dorsal striatum) and D4 and D5 receptors. It remains to be determined if D2 and D1 receptors function interactively in the population of neurons that expresses both DA receptor subtypes. The key to understanding whether these receptors function in a cooperative or antagonistic fashion will be a thorough understanding of the signal transduction pathways through which the different DA receptors operate. DA receptors have generally been classified on the basis of their effects on adenyl cyclase activity: D1 receptors stimulate whereas D2 receptors inhibit or have no effect on adenyl cyclase. Thus, one could explain antagonistic interactions. However, synergistic interactions between the two receptor subtypes presumably could not operate. However, recent studies have indicated that D1 receptors may work through more than one transduction system: D1 receptors that regulate phosphoinositol turnover in the kidney and striatum have been uncovered. Thus, the second-messenger systems through which ligand-receptor interactions affect intracellular mechanisms may be coordinately regulated in the case of D2-D1 interactions. Seeman and colleagues (21) recently examined the interactions between D2 and D1 receptors, and reported the absence of a D2-D1 link in a large percentage of postmortem striatal samples from schizophrenic subjects. D2 agonists reduce binding of [3H]raclopride to D2 receptors in striatal and pituitary membrane preparation; these data are consistent with the proposal that raclopride binding to the D2 receptor is subject to displacement by endogenous DA (22). The D1
significance
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antagonist SCH 23390 prevented the DA agonist-induced reduction in [3H]raclopride binding to D2 sites in the striatum but not adenohypophysis (which lacks D1 receptors). Conversely, DA agonist-induced decreases in the binding of [3H]SCH 23390 to D1 receptors was prevented by the D2 antagonist eticlopride (21). The ability of the D1 antagonist to block an agonist-elicited decrease in D2 receptor binding is similar to that produced by guanine nucleotides; this form of D2-D1 interaction therefore may be linked to G protein mechanisms. This D2-D1 link was absent in more than half of the striatal samples from schizophrenic subjects. However, there was also a defect in receptor interaction in striatal samples from patients with Huntingtons disease, but not in patients with Alzheimers or Parkinsons disease or in normal controls. The linkage of DA receptors to effect G proteins allows a means whereby interactions between receptor subtypes can occur in the same neurons. Moreover, recent data indicate that in human tissue multiple forms of both D2 and D1 receptors can be differentiated on the basis of guanine nucleotide effects on agonist binding, and that these different forms of receptor subtypes (which may or may not correspond to more recently cloned D2 and D1 isoforms) are (at least in part) localized to different neuronal populations (23, 24). Thus, there may be multiple mechanisms through which DA receptor subtypes interact. DA INTERACTIONS SYSTEMS WITH OTHER TRANSMITTER

The regulation of dopaminergic function in the brain occurs through processes intrinsic to DA neurons and via interactions with other neurons. In light of the inability to define conclusively an alteration in DA concentrations or DA receptor density in the brain of schizophrenic subjects, some investigators have suggested that the involvement of DA in schizophrenia is in response to a primary defect in some other neurotransmitter. In this model, the change in DA function represents a compensatory homeostatic response in neurons either downstream or anteceding the primary neuronal defect. Whether or not this hypothesis is correct, it is clear that the many aspects of DA neuronal function can be regulated by other defined transmitter systems. Such interactions may involve either classical transmitters (such as excitatory amino acids) or peptide transmitters. Interactions between dopamine and neuropeptides

The discovery of the coexistence of different neurotransmitters in single neurons has altered our basic concepts of the nature of information processing in the CNS. The ventral mesencephalic DA neurons have been among the most intensively studied of the coexistent neuronal populations. These neurons express DA and cholecystokinin (CCK), and DA and neurotensin (NT); frequently, all three transmitters are present in the same cell (25). Fuxe (26) has developed the concept of heterostatic regulation by following the regulation of D2 binding and its modification by peptides such as NT and CCK; the original in vitro studies have been recently extended with in vivo analyses (27). Neurotensin reduces the affinity of DA D2 agonist (3H-N-n-propylnorapomorphine) binding sites without affecting the characteristics of antagonist binding; although the magnitude of the change in receptor affinity is small, the effect is consistent. This type of receptor-receptor interaction is not due to displacement at the receptor site, but represents an interaction at the level of the peptide and dopamine receptors themselves.

Fuxe (26) hypothesizes that through such receptor-receptor interactions the set point of synaptic transmission can be altered without interfering with synaptic homeostasis? The receptor-receptor interactions appear to operate more efficiently when the DA receptor site is supersensitive. A direct examination of the degree to which receptor-receptor interactions are operative in both schizophrenic and control human brain remains to be determined. The presence of such heterostatic interactions would predict that basal release characteristics of DA would be normal, but the response characteristics of DA release to various perturbations might be exaggerated. Such a scenario might explain the lack of consensus on changes in basal DA concentrations in schizophrenia. The extrapolation of basic science findings from the rodent to the human is always fraught with difficulty. For example, NT-DA coexistence in AlO DA neurons and in axons innervating the medial prefrontal cortex of the rat is well established (28). However, recent immunohistochemical studies suggest that such coexistence may not be present in primate species, including humans (see refs 29, 30). Caution must be exercised before reaching a conclusion concerning the existence (or lack thereof) of both NT and DA in the same midbrain neurons. The opportunities afforded by the use of in situ hybridization histochemistry to localize specific mRNAs may help to resolve this issue. It is difficult to demonstrate unequivocally a lack of coexistence in primate species, as a variety of manipulations (such as colchicine pretreatment) must be made to ensure that the intraneuronal stores of the peptide are sufficiently high to allow detection using immunohistochemistry. However, it is exceedingly difficult to perform such manipulations in nonhuman primate species. The application of molecular approaches to the study of the human neurotensin gene may clarify the status of NT-DA coexistence in the primate. Applying in situ hybridization histochemistry to the question of CCK-DA coexistence in primate species, H#{246}kfelt and Schalling and colleagues (31) have made an intriguing observation in postmortem schizophrenic material. The presence of CCK in midbrain DA neurons in the rat has been well characterized (29). However, Palacios et al. (32) reported that CCK and TH mRNAs are not colocalized in neurons in the pars compacta of the human substantia nigra. Subsequently, H#{246}kfelt and associates (31) reported a relatively high degree of CCK gene expression in nigral DA neurons in the midbrain from schizophrenic patients (31). A comparison between schizophrenic and normal control postmortem material revealed that a relatively high number of CCK transcripts could be detected in neurons of human substantia nigra obtained from schizophrenic subjects; in contrast, very few of the normal control subjects had detectable CCK mRNA. However, the tissue examined came from schizophrenic subjects with a history of antipsychotic drug treatment. To determine if APD treatment could modify CCK gene expression in the midbrain, chronic administration of antipsychotic drug treatment to a variety of nonprimate species was undertaken; in no case did APD treatment induce or enhance CCK gene expression in the substantia nigra (31). Additional studies will be required to determine the rate at which CCK gene transcription occurs in schizophrenic and normal control subjects, and if transcription is modified by APD treatment. These intriguing findings of differential expression of the CCK gene in DA neurons of schizophrenic patients may accelerate novel approaches to the treatment of schizophrenia, including the development of drugs that modify peptide transmission yet gain relatively free access to the CNS.

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Dopamine-glutamate

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Over the past several years increasing attention has focused on the possible regulation of dopaminergic function by excitatory amino acids, particularly glutamate. A major impetus for this focus is the fact that the output of the cortex occurs-with the exception of a few peptidergic neuronsalmost exclusively via neurons containing an excitatory amino acid (EAA), such as glutamate, aspartate, or N-acetylaspartylglutamate. This fact, coupled with the belief that schizophrenia (in which formal thought disorder is prominent) has some cortical abnormality, has led to an increasing awareness of the means whereby cortical mechanisms may influence subcortical dopaminergic mechanisms (see below). Cognitive function is thought in large part to be cortical in nature. However, subcortical sites, including those in the striatum, also appear to be involved in cognitive function (see ref 33); such involvement may reflect corticostriatal function or, alternatively, may be manifested by striatal influences on other downstream targets. Carlsson and Carisson (34) have hypothesized that the cortex can control sensory input and thus arousal (which may be disturbed in schizophrenia; see ref 35) via the striatum, thalamus, and midbrain reticular core; this regulation of cortical sensory input and arousal presumably involves a number of functionally distinct circuits organized as parallel cortico-striato-pallido-cortical loops, each loop having a distinct spatial localization within each of the relay stations. The basic proposition in this model is that dopaminergic inputs to the striatal complex dampen the inhibitory influence of striatofugal neurons on thalamo-reticular projections that govern arousal in the cortex. Thus, if striatal dopaminergic tone is elevated (as the dopamine hypothesis of schizophrenia holds), there is an increased sensory input and arousal that can lead to disorganized thought processes. The key regulatory step by which striatal dopaminergic tone is posited to occur is via corticostriatal glutamatergic projections that inhibit DA release. Phencyclidine (PCP), an N-methyl-D-aspartate type EAA receptor antagonist, has been suggested to induce certain schizophrenic symptoms in some persons. The ability of PCP to induce catecholamine release is well documented. Accordingly, it is suggested that a decrease in corticostriatal glutamatergic transmission would enhance subcortical DA release, as does NMDA receptor blockade by PCP. Supporting this idea is the observation that in the virtually complete absence of dopamine an NMDA antagonist can enhance locomotion (36). Unfortunately, the precise interrelationships between striatal DA release and glutamate are not clear. Wachtel and Turski (37) have noted three hypotheses to account for the ability of PCP to induce a psychotic state and enhance DA release. However, many studies in which striatal glutamate levels were directly manipulated (rather than via systemic administration influencing glutamatergic systems globally) suggest that corticostriatal glutamate may actually serve to enhance DA release (38-40), and have led to the suggestion that increased (rather than decreased) glutamate influence over the striatum may underlie the positive symptoms of schizophrenia by evoking DA release in the ventral striatum (41). Indeed, direct infusion of 2-amino-5-phosphopentanoic acid, an NMDA antagonist, to the striatum via in vivo dialysis probes blocks glutamate-evoked DA release. The involvement of different EAA receptor subtypes (NMDA vs. nonNMDA [e.g., AMPA family] receptors) remains unclear. Although the precise nature of the interactions between glutamate and dopamine remains to be resolved, the apparent involvement of certain cortical sites in schizophrenia sugDOPAMINERGIC MECHANISMS IN SCHIZOPHRENIA

gests that interactions between the two transmitters a crucial role in the pathogenesis of schizophrenia.

may play

CORTICAL
MECHANISMS,

FUNCTION, AND

DOPAMINERGIC SCHIZOPHRENIA

Attempts to localize specific sites in the brain that are dysfunctional in schizophrenia have been undertaken by pathologists since the last century (see ref 42); some have suggested that this area of endeavor represents the graveyard of neuropathologists. Efforts of investigators to describe specific pathological foci in schizophrenia have traversed the same path as that subsequently followed by biochemists in a search for changes in DA concentration: initial reports followed by counterclaims and a general inability to replicate. However, the advent of modern anatomical methods, including immunohistochemistry, in situ hybridization histochemistry, quantitative morphometry, and in vivo imaging techniques, suggests that the graveyard of pathologists may turn into a treasure trove (43). Attempts to localize dopaminergic dysfunction in schizophrenia initially focused on the neostriatum, the area in the brain with the greatest DA concentration, and the ventral mesencephalic tegmentum, source of DA projections to the forebrain. These attempts arose after the initial statement of the DA hypothesis. The discovery of a dopaminergic innervation of cortical regions shifted attention to the definition of biochemical and anatomical abnormalities in the mesocortical DA system, and particularly within the prefrontal cortex. Although many studies have described changes in the cortex of schizophrenics, documented changes are the cell density in the cortex rather than the DA innervation. Such changes are consistent with the presence of enlarged ventricles in (certain) schizophrenic subjects. The ability to visualize brain anatomy in the living patient has revealed that many schizophrenic patients have enlarged ventricles (44, 45). Because enlarged ventricles usually occur at the expense of the cortex (leading to cortical thinning), it is not unreasonable to assume that there is an intrinsic cortical defect in schizophrenia. Local cerebral glucose utilization in schizophrenia

In vivo imaging methods have been used in studies of schizophrenic subjects to delineate structural, pharmacological, and physiological changes. Although the spatial resolution of such methods is clearly limited, the ability to define changes within certain regions of the brain and indeed delineate interactive circuits in patients offers a unique oportunity. Tamminga and co-workers (46, 47) have examined local cerebral glucose utilization (LCGU) in actively psychotic schizophrenic subjects not on APD treatment at the time of the scan. Overall, schizophrenic subjects showed reduced LCGU in several limbic regions, but not in neocortical or extrapyramidal areas; in particular, a decrease in LCGU was observed in the hippocampal region and anterior cingulate cortex. Tamminga (47) subsequently divided schizophrenic patients into those with a deficit or nondeficit state. In the deficit patients, LCGU was decreased in the thalamus and frontal and parietal cortices; these areas exhibited normal metabolic status in the nondeficit group of patients. Both deficit and nondeficit patients exhibits hippocampal and anterior cingulate hypometabolism. Physiological dysfunction is therefore present in different neuronal circuits in deficit and nondeficit state schizophrenics, but there is a core change in metabolism in the anterior cingulate area and hippocampal region of all patients. 2417

LCGU measures are thought to predominantly reflect metabolism of nerve terminals, and thus LCGU is usually interpreted to indicate that changes in a particular structure are a reflection of the functional status of afferents to the region. As such, one might expect that LCGU measures would give somewhat different results from other in vivo imaging techniques. For example, Tamminga (47) described how the overall group of schizophrenic patients she examined had no change in neocortical sites; neocortical hypometabolism became apparent only when the deficit state patients were examined. However, there could be deviations from normal in the function of key neocortical sites which project to the anterior cingulate/hippocampal regions. The dorsolateral prefrontal cortex in schizophrenia

Studies using a different method for the in vivo assessment of changes in energy metabolism in schizophrenia clearly suggest a functional impairment in the prefrontal cortex (PFC). Thus, Weinberger, Berman, and associates (see ref 48) have described how cerebral blood flow in the dorsolateral PFC is augmented in normal subjects under the conditions of a task thought to specifically reflect prefrontal cortical function (the Wisconsin Card Sort Task); the normal increase in blood flow is dampened in schizophrenic subjects. These data may be reconciled with those of Tamminga et al. (47) on the grounds of examination of different dependent measures (cerebral blood flow vs. LCGU) and the task-dependent nature of the changes described by Weinberger and Berman (48). In addition, studies by Tamminga (47) clearly indicate the importance of defining patient characteristics. Based in part on the task-specific changes in PFC blood flow in these data, Weinberger (49) has elaborated a neurodevelopmental theory of schizophrenia. This theory posits a functional decrease in DA in the PFC, noting that cognitive deficits are seen after lesions of the PFC DA innervation in primates (50). Negative symptoms are specifically suggested to arise because of the cortical DA lesion: whereas florid positive symptornatology (which can be treated with relative success by conventional antipsychotic drugs) occurs because of excess dopaminergic tone in subcortical sites, including the nucleus accumbens. The increase in DA tone in subcortical sites is suggested to occur as a result of a functional decrease in DA in the PFC, thereby removing corticofugal glutamatergic neurons from tonic DA-mediated inhibition (6, 51). Recent data suggest that DA depletion in the PFC can indeed remove corticostriatal glutamate neurons from inhibition, and thereby evoke a transsynaptic increase in DA release in the ventral striatum. Deutch and associates (41, 52, 53) have shown that although PFC DA lesions do not appear to increase basal DA release in subcortical sites, they do enhance responsiveness of the mesolimbic DA innervation to both environmental perturbations (mild stress) and pharmacological challenge. The PFC has been the most extensively studied of the cortical areas in terms of regulation of subcortical function. However, recent data have emphasized a structural defect in temporal lobe sites, including the hippocampus and entorhinal cortex (54, 55). These data are also consistent with the LCGU findings (47): the entorhinal cortex provides the major input to the hippocampus. As these temporal lobe areas also project to the ventral striatum, decreases in DA in these limbic cortical areas might also be expected to increase accumbal DA responsiveness. Such a change may be manifested in discrete parts of the accumbens, such as the shell region (56). The entire cortical mantle projects onto the striatum in a topographically defined manner; changes in cortical function should therefore result in transsynpatic alterations in striatal function, but within discrete defined striatal sectors.

Although it appears that functional or structural defects in the dopaminergic innervation of cortical sites may be manifested by increasing subcortical dopaminergic tone, recent postmortem studies and in vivo imaging studies suggest that there may be cortical tissue loss in schizophrenia. How can one correlate such a structural deficit with increased subcortical DA tone? The loss of cortical thickness can result from deafferentation or, alternatively, from decreases in the number of cortical neurons. In the latter case, it is difficult to envision how such a decrease in corticofugal neurons could be translated into increased glutamatergic release subcortically, thereby increasing DA tone. One possibility is that the loss in neurons in the cortex is restricted to interneurons rather than projection neurons (57). Alternatively, if some glutamatecontaining neurons of the cortex that project to the striatal complex are lost, it is conceivable that residual neurons are hyperactive; coupled with a decreased reuptake mechanism for the amino acid, a relative hyperglutamatergic state might be present. Obviously, these are speculative notions, and future work will be needed to resolve the nature of glutamatergic-dopaminergic interactions in both the normal brain and in schizophrenic brain.

MECHANISMS DRUGS

OF

ACTION

OF

ANTIPSYCHOTIC

One cornerstone of the DA hypothesis of schizophrenia is the observation that all known clinically effective antipsychotic drugs are antagonists at the D2 DA receptor (see refs 58, 59). Although this does not exclude actions at other receptors from modifying the actions of APDs, it would appear that antagonism at some D2 receptor isoform is necessary for antipsychotic action. Moreover, because drugs such as sulpiride and raclopride are thought to be selective D2 agents, action at a D2 site may be both necessary and sufficient for antipsychotic activity, and indeed for atypical antipsychotic drug action (58). This does not mean that interactions with other receptors (such as the 5-HT2 receptor; see ref 59) cannot modify the nature of the clinical actions of APDs, rendering them more (or less) effective for certain symptom constellations or changing their side-effect profiles. Indeed, there may be more than one way to achieve an atypical APD profile (58). Elucidation of the mechanisms subserving the atypical APD profile (clinical efficacy and very low or absent extrapyramidal side effects [EPS; see ref 58]) have been a major focus of study over the past several years. This has been prompted in large part by the introduction of clozapine, which is effective in schizophrenic patients refractory to conventional neuroleptics, and also appears to be of considerable use in the treatment of negative symptoms. Unfortunately, clozapine is also marked by a relatively high incidence (1-2%) of agranulocytosis. Ogren and colleagues (60, 61) have been instrumental in the characterization of novel APDs with low or absent EPS liability. A useful notion that has emerged from their behavioral studies is that atypical APDS have a very wide separation between the ED50 required to reverse apomorphine-induced locomotion and the ED50 for eliciting catalepsy; in contrast, the doses of typical APDs (neuroleptics) effective for the two behavioral endpoints are much closer. Using these behavioral measures, one can dissociate known and potential atypical APDs (clozapine, remoxipride) from neuroleptics (haloperidol). These animal behavior screens have proved useful in predicting the ultimate clinical outcome of putative APDs.

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Analysis of the receptor mechanisms of drugs that have a wide separation between the ED50s for reversal of agonistinduced locomotion and catalepsy suggest that interadion at some D2 isoform may be the key mechanism for an atypical profile. Thus, Ogren et al. (62) have shown that the actions of substituted benzamides such as remoxipride, an atypical APD, cannot be accounted for on the basis of blockade of 5-HT2, muscarinic, or adrenergic receptors. If an atypical APD profile can be achieved by action at D2 receptors, such a hypothesis must explain the typical neuroleptic profile of the selective D2 antagonist sulpiride. Two recent findings may resolve this apparent discrepancy. The first is the cloning of multiple D2-type isoforms: typical and atypical APDs may interact with different isoforms of the DA D2 receptor. It is not clear to what degree such isoforms may correspond to the currently known D2 forms, such as the socalled D4 receptor. However, examination of the receptor binding profile of an expressed D4 suggests that the pharmacology cannot explain all atypical APDs. The second explanation may lie in atypical APDs interacting with different D2 isoforms that are heterogeneously distributed in the brain; recent data suggest that the alternative splice products of the original D2 receptor clone (4) may be expressed to different degrees in different brain regions, as are other cloned D2type receptors. Accordingly, it might be possible to discern reginally specific changes in DA release or metabolism that underlie the actions of atypical APDs. Important regional differences in the actions of typical and atypical APDs on DA function are present. Bunney and coworkers (63), using electrophysiological methods, have described the different effects of an atypical APD (clozapine) from neuroleptics (such as haloperidol). Chronic administration of the latter results in depolarization inactivation of DA neurons in both the A9 (substantia nigra) and AlO (ventral tegmental area) DA neurons, whereas chronic administration of clozapine results in depolarization inactivation only of AlO DA neurons (see ref 63). The latter effect may, in part, explain why clozapine has a very low propensity for the induction of EPS. More recently, Bunney and Moghaddam (64, 65) used in vivo microdialysis to assess DA release in different brain areas in response to acute administration of typical and atypical APDs. The neuroleptic sulpiride increased DA efflux in the striatum and nucleus accumbens but not in the prefrontal cortex, even at doses as high as 100 mg/kg (i.v.). Haloperidol also resulted in a large increase in DA release in the striatal and mesolimbic sites, but in contrast had only a transient effect in the PFC, and then only at the highest dose. Thus, both neuroleptics strongly increase striatal and mesolimbic DA release but exerted little or no effect on PFC DA release. This stands in sharp contrast to the atypical APD clozapine, which markedly increased PFC DA release; clozapine also increased release of the amine from mesolimbic sites and to a lesser degree from the striatum. These data suggest that clozapine and perhaps other atypical APDs can be distinguished from neuroleptics such as haloperidol and sulpiride on the basis of greater action at cortical sites. If the preferential effect of acute clozapine on cortical DA release is sustained under chronic administration, such results may help explain the fact that clozapine is useful in treating negative symptoms; these symptoms have been suggested to arise as a consequence of DA deficiency in the prefrontal cortex (49). Characterization of the regionally selective effects of typical and atypical APDs on DA release have been restricted to examination of only a few brain structures. It will be of interest to determine whether other cortical sites (e.g., temporal lobe structures) show response characteristics similar to those of the PFC. It will also be important to define the

actions of typical and atypical APDs on different DA systems within a single structure, such as the striatum. The islandic and diffuse DA innervations of the caudatoputamen can be differentiated on the basis of ontogenetic characteristics, morphology, responses to a certain ergolene derivatives, and spatial relationships with the patch (striosomal) and matrix compartments of the striatum as defined on the basis of other histochemical markers. Fuxe and Ogren (66) recently observed that the atypical APD remoxipride exerts selective effects on DA release in the diffuse DA innervation of the medial striatum; distinct compartmental effects of remoxipride on striatal c-fos expression have also been seen (67). These data may suggest that different DA D2 receptor forms are present not only in different brain regions, but also within different classes of neurons within a given area.

CONCLUSIONS The DA hypothesis of schizophrenia remains a hypothesis. The most compelling data marshalled in support of the hypothesis are still in relationship between APDs and D2 receptors, and the existence of psychostimulant-induced psychoses. It has been difficult to determine to what degree the DA hypothesis is one of schizophrenia, as opposed to one of psychosis. Whereas the basic structure of the DA hypothesis remains intact, increasing emphasis has been placed on the modes of regulation of DA neurons; these regulatory aspects include features intrinsic to the neuron as well as extrinsic regulatory controls, such as afferents. In turn, there is a growing awareness of the importance of interactions of DA with other defined transmitter systems. New methods allowing in vivo assessment of structural, physiological, and pharmacological changes in schizophrenia, albeit on a limited spatial resolution, have led to a shifting of emphasis from discrete sites to neural systems that may be affected in different forms of schizophrenia. These recent advances in our knowledge of the ways through which DA systems are regulated, from the most basic molecular biology to the most elaborate systems approaches, are illuminating new paths for the development of treatment strategies for schizophrenia. We appreciate the expert secretarial assistance of Ms. Judi Scheer. This work was supported in part by grants MH-43230 (M. G.), MH-027l7 (M. G.), and MH-45l24 (A. Y. D.), and by the Veterans Administration National Center for Schizophrenia Research, West Haven Veterans Administration Medical Center, West Haven, Connecticut (A. Y. D.). REFERENCES 1. Seeman, P., and Niznik, H. B. (1990) Dopamine receptors and transporters in Parkinsons disease and schizophrenia. FASEBJ 4, 2737-2744 2. Farde, L., Wiesel, F-A., Stone-Elander, S., Halldin, C., Norstrom, A.-L., Hall, H., and Sedvall, G. (1990) D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [uClraclopride. Arch. Gen. Psychiatry 47, 213-219 3. Wong, D. F., Wagner, H. N., Jr., Tune, L. E., Dannals, R. G., Pearison, G. D., Links, J. M., Tamminga, C. A., Broussolle, E. P., Ravert, H. T., Wilson, A. A., Toung, J. K. T., Malat, J., Williams, J. A., OTuama, L. A., Snyder, S. H., Kuhar, M. J., and Gjedde, A. (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234, 1558-1563 4. Bunzow, J. R., Van Tol, H. H. M., Grandy, D. K., Albert, P., Salon, J., Christie, M., Machida, C. A., Neve, K. A., and

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