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Limbic/Mesolimbic Connections and the Pathogenesis of Schizophrenia John G. Csernansky, Greer M. Murphy, and William O. Faustman

The development of models of the pathogenesis of neuropsychiatric diseases that build on recent advances in chemical neuroanatomy will help to guide future research. The interconnections among limbic, basal ganglia, and cortical structures are used to form ~he basis of a hypothesis of the pathogenesis of schizophrenia. The adaptiv capacity of subcortical dopamine systems is advanced as an explanation of the matt), states of the disease.

Introduction Despite more than 30 years of intense researcb~ much remains to be learned about the biology of schizophrenia. No pathogenetic mechanism has yet been proposed that can satisfactorily explain the many symptoms and states of the syndrome. The dopamine (DA) hypothesis, originally derived from the observation that neuroleptics increase brain DA turnover, proposed a general overactivity of DA systems (Carlsson and Lindqvist 1963). During the 1970s, the hypothesis became more refined as the mesolimbic DA pathway was specifically proposed as the site of action of antipsychotic drugs (Stevens 1973). Furthermore, by that time many schizophrenia experts believed that DA function might be abnormally increased in only some patients or circumstances and decreased in others (Wyatt 1986), and that any alteration of DA function in schizophrenia was most likely secondary to some other abnormality (Meltzer and Stahl 1976). In a recent update of the classical DA hypothesis, the connections between midbrain DA neurons and other neurotransmitter systems in the basal ganglia, thalamus, and cortex have been stressed, and a failure of cortical glutamatergic projections to modulate ascending mesolimbic DA pathways has been proposed as the primary abnormality (Carlsson 1988; Carlsson and Carlsson 1990). According to this theory, glutamatergic underactivity may lead directly to pathological increases in behavior (i.e., psychosis). Luchins (1990) and Reynolds (i989) have rec~;ntly proposed similar theories, but have emphasized the hippocampus and its glutamatergic projections to the nucleus accumbens and amygdala, respectively.

From the Department of Psychiatry, Washington University School of Medicine. St. Louis, Missouri (JGC); Aging Clinical Research Center. Palo Alto VA Medical Center, Palo Alto, California (GMM); Stanford University School of Medicine, Stanford, California (WOF). Address reprint requests to John G~ Csemansky, M.D,, Gregory Couch Associate Professor of Psychiatry, Washington University School of Medicine. Department of Psychiatry, 4940 Audubon Avenue, St. Louis, MO 63110. Received November 11, 1989; revised February 14, 1991, © 1991 Society of Biological Psychiatry

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Nonetheless, schizophrenia is a waxing and waning disease, with periods of behavioral deficit as wel~ as psychosis. These most recent updates of the DA hypothesis, despite their advantages, do not explain what process drives such changes in the clinical picture. Friedhoff has long proposed that the adaptational capabilities of DA neurons and the postsynaptic cells on which DA receptors reside must be centrally involved in the patbogenesis of schizophrenia. In a recent update of this perspective, Friedhoff (1988) proposes that adaptive decreases in DA transmission may be required to restore normality of brain function in normals and in many schizophrenics, but that in a significant subgroup (i.o., neuroleptic responders) this homeostatic system is defective. Although this hypot'aesis does not fully integrate these changes in DA function into a larger anatomical context, it offers certain advantages as up and down adaptations in DA function could plausibly explain the many states of the disease. Weinberger (1987) ha~ suggested, as an alternate hypothesis, that schizophrenia is first and foremost a disease of the dorsolateral prefrontal cortex, and that negative symptoms and cognitive abnormalities are brought about by damage to this structure and the mesocortical DA system that innervates it. Psychotic symptoms are then attributed to the "normal," reciprocal overactivation of subcortical DA systems (Pycock et al 1980). This hypothesis is enhanced by the specific Froposal that abnormalities of dorsolateral prefrontal c~rcuits would only become apparent later in life, near the typical age of onset of schizophrenia, due to normal brain niaturational events. However, direct support for this hypothesis depends on the success of curren: attempts to demonstrate primary neuroanatomical abnormalities of the prefrontal cortex in at least a significant subgroup of schizophrenic patients. Models of the pathogenesis of schizophrenia that can integrate recent neuroanatomical advances are needed to guide future research. The purpose of this paper is to consider a model that stresses the importance of limbic structures, the projections of these structures to the basal ganglia and cerebral cortex, and the modulation of these limbic projections by DA in understanding the pathogenesis of at least some forms of schizo-. phrenia. We propose that increased and disorganized activity, rather than a deficit of limbic glutamatergic projections to the nucleus accumbens triggers a series of changes in subcortical DA transmission. We suggest that baseline decreases in mesolimbic DA transmission underlie the prodromal and residual states of the illness, but that transient increases in DA transmission coupled to postsynaptic DA D2-receptor supersensitivity occur to produce psychotic episodes. The connections among limbic, basal ganglia, and cortical structures will be briefly reviewed along with an explanation of the hypothesis. Then a discussion of functional interactions among these structures during normal functioning and experimental perturbations of limbic function in animals will be cited as support. Finally, recent evidence from neuropathological, neuropsychoiogical, and neurochemicai studies in schizophrenic patients will be considered.

Hypothesis To simplify this discussion, the ongoing course of schizophrenia will be divided into two predominant states: (1) the prodromal/residual state and (2) the exacerbated state (i.e.. psychotic relapse). We postulate that the prodromal and residual states are similar, although there is little evidence to address the issue, as longitudinal studies of schizophrenic patients that include an assessment of the time period prior to their first psychotic episode have not been done. These two states are characterized by negative

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and oositive symptoms, respectively. The validity of these symptom categories has been estabZshed by several groups (Andreasen and Olson 1982; Carpenter et al 1988; Crow 1985; Pogue-Geile and Harrow 1985) F~gure 1 illustrates a circuit of anatomical connections between the amygdala/ h~pp~ampus '-'nd cingulate cortex through d~e nucleus accumbens that is concepWally analogous to the overlapping cortical/subcortical circuits described by Alexander et a! (1986). However, in this case the hippocampus and amygdala are considered the primary "cortical" structures. There are multiple interconnections between the amygd:da and hippocampus (Amaral 1986); and between the hippocampus and cingulate cor:iex Ode and Markowitsch 1982). This anatomical view is also consistent with the interpretations of anatomical data recently made by Alheid and Heimer (1988). To briefly summarize the anatomy of this circuit, the amygdala and hippocampus bozh send projections to the nucleus accumbens and ventromediat 2ortion of the caudate nucleus (DeFrance et al 1980; Yim and Mogenson 1982; Nauta and Domesick 1984; Amaral 1986). As with corticostriatal projections, these are glutamatergic and

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excitatory (Fuller et al 1987). The nucleus accumbens and ventromedial caudate in turn send inhibitory GABAergic projections to the ventral pallidum (Dray and Oakley 1977; Williams et al 1977; Jones and Mogenson 1980a, 1980b). Inhibitory GABAergic neurons in the ventral pa!!idum then project to the dorsomedial nucleus of the thalamus (Graybiel 1984; van Eden 1986; Vives and Mogenson 1985). Output from the dorsomed,.'al nucleus of the thalamus is projected to the cingutate cortex (Goldman-Rakic and Porrino 1985), along with the dorsolateral, medial, and ventral prefrontal cortices, and the supplementary motor cortex. In general, the projectioae from thalamic nuclei to cortex are monosynaptic (Steriade and Glenn 1992) and excitatorj (Steriade and Deschenes 1984, see also Graybiel 1990). For cortical projections from the intralaminar and ventromedial thalamic nuclei, the neurotransmitter appears to be glutamate or aspartate (Ottersen et al 1983). The hippocampus/amygdala and cingulate cortex are interconnected with a variety of cortical structures (Salter and Markowitsch 1984; Aggleton et al 1980; Russchen et al 1987; LeDoux 1987; Goldman-Rakic et al 1984; Selemon and Goldman-Rakic 1988; Van Hoesen 1982). The hippocampus also projects to the cingulate cortex through the manunillary body and ,-interior thalamus (Aggleton et al 1986). Furthermore, the arnygdala forms another circuit involving the dorsomedial thalamus and o~bitofrantal cortex (Goldman-Rakic and Porrino 1985). Ventral tegmental area (VTA) DA r~eu,~ons modu!ate the activity of this circuit through projections to the nucleus accumbens, ventromedial caudate, and the hippocampus/amygdala (see Moore and Bloom i978 for review). Activation of this limbic circuit through hippocampal excitation inhibits ongoing behavior in animal models and presumably in humans (see below). However, mesolimbic DA function modulates the release of this behavior through inhibition of the circuit (see Figure 2, normal state). For schizophrenic patients in the prcn]romal/residual state, we propose that the circuit's activity is abnormally increased, due to ;.he following changes. First, we suggest that congenital abnormalities of limbic structure cytoarchitecture (see evidence below) would cause chronic increases in the activity of excitatory glutamatergic projections to the nucleus accumbens. Then, secondary to this glutamatergic increase, the level of mesolimbic DA transmission would become reduced (see Figure 2, prodromal/residual state). Decreases in DA transmission following increases in glutamatergic projections to the nucleus accumbens are inconsistent with the ability of glutamate to increase DA release when it is infused directly into the nucleus accumbens (see Cheramy et ai 1990 for review). However, this DA response is consistent with the ability of glutamatergic projections to the VTA, through GABA intemeurons, to decrease the firing rate of DA neurons (see Carlsson and Carlsson 1990). Next we propose that, in a manner analogous to the upregulation of DA D2 receptors triggered by surgical or neuroleptic-induced denervation, ircreases in the density of postsynaptic DA D2 receptors would become coupled "o chronic decreases in the availability of DA (see Seeman 1980 for review of neuroleptic-induced DA receptor upregulation). Then, when DA transmission is acutely increased secondary to environmental stressors (for animal experiments see Blanc et al 1980; Roth et al 1982; Antelman and Chiodo 1984), the disinhibition of this limbic circuit by DA would ~ suddenly reversed, leading to pathological releases of behavior (i.e., psychosis) (see Figure 2, exacerbated state). Although oversimplifying the relapse process, environmental stressors often precede psychotic relapse in schizophrenic patients (Birley and Brown 1970; Herz and Melville 1980).

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Evidence for the Hypothesis

Normal Functional Interactions Within the Circuit In rodents, the electrica! activation of GABAergic nucleus accumbens neurons inhibits locomotion (Jones and Mogenson 1980b). Direct injections of N-methyl-D-asparate (NMDA) into the striatum also inhibit movement (Schmidt and Bury 1988), while NMDA antag-

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onists stimulate ongoing locomotion (Schmidt 1986). Likewise, injections of NMDA into ~he rat amygdala inhibit spontaneous locomotion (Yim and Mogenson 1989). Consistent with this latter observation, bursts of abnormal electrical activity that occur during temporal lobe seizures in h:,mans can also produce abrupt interruptions of ongoing behavior (Gloor 1986). This type of evidence suggests that in the primate brain, activation of the circuit from the hippocampus and amygdala through the nucleus accumbens inhibits ongoing behavior or cognition in some fashion, perhaps in order to reorient the individual to new incoming sensory information. Nucleus accumbens GABA neurons that receive excitatory glutamatergic projections from the hippocampus/amygdala also receive ascending DA projections from the VTA (Graybiel 1984; Totterdell and Smith 1989). Although the exact neurophysiological mechanisms remain under investigation, the stimulation of VTA DA neurons, or a direct injection of DA into the nucleus accumbens, d~.,:reases the firing rate of nucleus accumbens GABAergic neurons (Yim and Mogenson 1982). This probably occurs via a direct antagonism between DA and glutamate projections that synapse on dendrites of nucleus accumbens neurons (Mogenson et al 1987; Totterdeil and Smith 1989). A recent elecUon microscopic study of hippocampal and midbrain catecholaminergic projections to the nucleus accumbens has shown that they can converge onto the same dendrites, and that their membranes can be in direct apposition (Sesack and Pickel 1990). In addition, the capacity of DA to antagonize the stimulation of nucleus accumbens neurons by limbic projections is inversely correlated with firing rate (Mogenson et al 1987).

Functional Interactions Following Limbic Perturbation We have hypothesized that abnormalities of subcortical DA function, particulally in the mesolimbic DA pathway, could be caused by chronic increases and disorganization of hippocampal or amygdala function. Cytaarchitectural neuronal abnormalities in the hippocampus or amygdala might bring about gross increases in the. firing rate or a disorganization of firing patterns (e.g., increased tandem sp~:es) of glutamatergic neurons. To deve!op an animal model of this typ~ ~ : ~j;~ph~c disturbance, we have used several methods to establish ongoing limbic cpiieptiiorm activity. Ferric chloride is a neuronal irritant, and when injected into the amygdala produces ongoing electrographic disturbances (e.g.0 spikes, bursts of slow waves) and behavioral convulsions for several weeks (Csernansky et al 1985). Animals injected into the amygdala with ferric chloride develop increases in DA D2-receptor densities in the nucleus accumbens ipsilateral to the site of the injection. This neurochemical response cannot 'be attributed to physical destruction of amygdaloid tissue by ferric chloride, as carbamazepine can block the ongoing epileptiform activity and the DA D2-receptor upregulation (Csernansky et al 1986). Ferric cMoride-injected animals also become behaviorally supersensitive to direct DA agonists, and show spontaneous stereotypic behavior (Csernansky et al 1985). Electrical kindling of the amygdala or hippocampus also results in chronic increases in neuronal excitability and electrographic background (King et al 1985), upregulation of DA D2 receptors in the ipsilateral nucleus accumbens and amygdala, and behavioral supersensitivity to DA agonists (Csemansky et al 1988a, 1988b). Electrical kindling may be a superior model for inducing ongoing electrographic disturbances in limbic structures, because it very clearly does not result from gross tissue destruction (see Racine et al 1984 for review). R~.ther, kindling develops following subtle rearrangements of neuronal

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connections within several limbic structures, particularly the hippocampus (Sutula et al 1988). Modest degrees of neuronal loss have also been observed in kindled animals, and may precede this synaptic reorganization (Cavazos and Sutula 1990). Upregulation of nucleus accumbens DA D2 receptors following electrical kindling of the hippocampus persists for at least two weeks following the last kindled seizure (Csemansky et al 1988a), and is accompanied by reciprocal decreases in DA turnover (Csernansky et al 1989). Acute seizures in kindled animals may produce additional DA turnover decreases in the nucleus accumbens and increases in the prefronta t cortex (Rada and tlernandez i990). Gross hippocampal lesions, like prefrontal cortical lesions (Pycock et al 1980), have also been shown in some studies to produce an upregulation of mesolimbic DA D2 receptors (Schmajuk 1987). However, the kindling data above clearly indicate that a "lesion" per se is not required to produce this phenomenon.

Studies #l Schizophrenic Patients Neuropathological Abnormalities. There is no single neuropathological fi:'.ding that is pathognomonic for schizophrenia. However, there is growing evidence that a variety of anatomical abnormalities occur in limbic structures in schizophrenic patients. Brown et al (1986) have reported that the parahippocampal cortex is thinner in postmortem schizophrenic brains compared to controls. Falkai et al (1988) reported the similar finding of a decreased cross sectional area in the entorhinal cortex of postmortem schizophrenic brain compared to controls. In addition, gross rearrangements of the three temporal gyri have been found (Bruton et al 1990). Finally, recent in vivo magnetic resonance imaging studies have shown grossly decreased cross sectional temporal lobe areas (DeLisi et al 1988; Kelsoe et al 1988; Bogerts et al 1990; Rossi et al 1990). In some studies, greater degrees of abnormality have been found in the left hemisphere (Crow et al 1989; Bogerts et al 1990). Light-microscopic findings of neuronal atrophy and gliosis have also been reported in limbic and mesolimbic subcortical structures in some (Stevens 1982; Bruton et al 1990), but not all (Casanova et al 1987; Stevens et al 1988) studies. In addition to indications of decreased tissue quantity or deterioration, cytoarchitecturzl anomalies in the hippocampus and other limbic circuit structures have been reported. Kovelman and Scheibel found disturbances in the spatial orientation of hippocampal pyramidal cells in schizophrenic brains collected at UCLA compared to controls (Scheibel and Kovelman 1980; Kovelman and Scheibel 1984). Although an attempt by these investigators to replicate thi~ finding using the Yakovlev Collection failed to confirm the original group difference, a relationship between the degree of hippocampal pyramidal cell disorientation and the severity of the illness was still found (Altshuler et al 1987). Jakob and Beckmann (1986) have also reported gross and microscopic structural abnormalities in the hippocampus of schizophrenics suggestive of neuronal misarrangement. More recently, Heinsen and Beckmann (Heinsen and Beckman or~.! presentation, ACNP Annual Meeting, December 1988) have reported decreased neur~:~nal numbers and heterotopic nests of cells in certain areas of the hippocampus and perirhinal cortex. Jeste and Lohr (1989) have reported decreased neuronal densities throughout the hippocampal pyramidal cell fields (CAI through CA4). Finally, Benes and her collaborators have reported decreased neuronal densities in the prefrontal, cingulate, and motor cortex of schizophrenic brain compared to controls (Benes et al 1986). In the cingulate corte~:, this

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finding was associated with an abnormal ordering of neuronal clusters (Benes and Bird 1987), and increased numbers of vertical axons (B~es et al 1987). In sum, the anatomical findings in the schizophrenic brain suggest that limbic circuit structures are consistently involved (Roberts 1990), and that the causative processes of schizophrenia occur during central nervous system development (Lyon et al 1989). However, these findings give us little ~rfform..at;o~ aboot 'what functional irregularities might exist in schizoph~enic patients. These findings do suggest that functional abnormalities of limbic structures in schizophrenia might not be similar to the abnormalities of function typically found following focal brain lesions. In rodent models of central nervous system development, insults to the hippocampus produced by hypoxia, ischemia, or by the administration of cytotoxic DNA polymerase inhibitors that produce analogous degrees of neuronal drop-out and misa~rangemeat have been studied. Increases in subcortical DA release (Silverstein and Johnston 1984; Lun et al 1986), hyperlocomotion (Gray et al 1986), and susceptibility to limbic epileptogenesis (DeLeo et al 1988) have been observed. It should be kept in mind that signs of brain tissue decreases or neuronal degeneration have been found in other cortical st:'uctures (see Maser and Keith 1983 for partial review; Pfefferbaum et al 1988) and in the cerebellum (Heath et al 1982) of schizophrenic patients. Thus, the abnormalities in the temporal lobe described above cannot be considered unique. However, while one would expect an insult during brain development to cause abnormalities in many brain areas (Lyon et al 1989), it is not unreasonable to propose that changes in certain brain areas could be specifically related to the production of schizophrenic symptoms. ,..,,~,~,.~' . . . . k. ;~,,,,,,,,,..'~'o-b~;,~,,, . . .~. . ~. might be highlv, variable among patients and so produce no consistent pattern of symptoms across groups of patients. Alternatively, changes in these other brain areas could underlie some of the nonspecific neuropsychia~c phenomena found in schizophrenic patients (e.g., soft neurological signs) or have consequences not yet recognized.

Clinical and Neuropsychological Abnormalities. The neurobiology and treatment of the negative symptoms of schizophrenia have been given greater attention recently. These clinical phenomena might be referable to deficits in many different brain areas, including the limbic system. The symptoms of impaired affect, social withdrawal, and apathy are similar to those observed in nonhuman primates subjected to gross amygdala/orbitofrontal lesions (Kling 1986). Work by several investigators (Tyack and Levin 1988; Levin et al 1985) suggests that schizophrenics are impaired in the vocal communication of affect. Walker et al (1984) have shown that schizophrenics have impairments in discriminating and labeling emotional cues, a capacity usually attributed to the amygda!a (LeDoux 1987). Although there has been longstanding recognition that schizophrenics perform poorly on neuropsychological tests, there have been no consistent findings that suggest a gross or focal lesion. Attentional impairment in schizopt~renia may be common (see Levin et al 1989 for review), with some theories advancing a lack of a sufficient initial filter to process sensory input. Others (Mirsky 1988) have suggested a broad range of attentional deficits (e.g., encoding, set shifting, sustaining attention). As multiple brain structures, such as the hippocampus, cingulate cortex, and prefrontal cortex, may underlie attention (Mirsky 1988), attentional measures may be especially sensitive to brain damage. Schizophrenics show impairments in memory functions thought to be subserved by the hippocampus and amygdala (Lezak 1983). In particular, schizophrenics show impairments in both verbal and visual modalities of memory functioning (Kolb and Whishaw 1983), a pattern of deficits suggestive of bilateral hippocampal involvement (Levin et al

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1989). Of course, memory impairments in schizophrenia must control for impairments in initial encoding as a result of inattention. Gruzelier et al (1988), have provided evidence of a temporo-hippocampal and fronto-hippocampal deficit pattern in schizophrenia, and others have implicated tenlporo-frontal or fronto-temporal deficit patterns (Taylor et al 1979; Taylor and Abrams 1984). Standardized test batteries, such as the Luria-Nebraska Neuropsychological Batter), (LNNB) may also add useful information in that they provide a broad and replicable assessment with known reliability and validity (Moses and Maruish 1988). Moses and Golden (1980) found that neurologically impaired patients tend to display greater cognitive deficits than schizophrenics on all but four LNNB scales (C2-rhythm, C5-receptive speech, C10-memory, and C1 l-intellectual processes). In other studies, sch;zophrenic patients showed the greatest relative impairment on these four LNNB scales (Moses 1983; Faustman et al 1989). Elevations on these LNNB measures are not consistent with any known cortical lesion locus, but may be consistent with a subcortical or limbic deficit pattern. Recent work (Goldberg et al 1987; Goldberg and Weinberger 1988) also suggests that schizophrenics show dorsolateral prefrontal cortical dysfunction, as reflected by specific impairments on the Wisconsiri Card Sort (WCS) test. A correlation has also been found between some frontal neurological soft-signs and the severity of negative symptoms (Merriam et al 1990). However, Robinson et al (1980) noted that WCS deficits are as profound in patients with diffuse brain pathology as in patients with specific frontal lesions. Heinrichs (1990) also noted that multiple indices of WCS performance were strongly correlated with total intelligence quotient measures derived from the Wechsler Adult Intelligence Scale-Revised in a mixed neuropsychiatric sanqple, suggesting that general intellectual ability may influence the skills required to perform the WCS. Other recent work (Braff et al 1991) suggests that schizophrenics who do poorly on the WCS also have deficits on multiple cognitive measures. Further work that can integrate experimental and clinical neuropsychological approaches is aie¢ded. Classic studies using neurologic samples (Scoville and Milner 1957; Milner 1971; Milner 1972) have delineated recognizable frontal (e.g., difficulty in set shifting/perseveration) and temporal lobe (verbal and visual memory) impairment patterns. The relative impairment or sparing of these functions have not been fully explored in schizophrenia, especially when one considers the need to address sampling bias in the selection of patients. In sum, schizophrenic patients show a range of d~ficits in memorial, attentional, and executive cognitive functions that are consistent with limbic dysfunction. ,n~lso,the deficits in most patients are not as severe as in neurologic samples (Moses 1983) and do not mimic patients with syndromes originating from discrete brain lesions. If limbic abnormalities in schizophrenia are derived from developmental aberrations, the consequent deficits would likely assume this type of complex deficit pattern. Neurochemical Alterations of Mesolimbic DA Function. Alterations in mesolimbic DA function (low to high to low) are a central feature of our hypothesis. Neurochemical studies of DA function in schizophrenia remain conflicted (Wyatt 1986), perhaps because only indirect means of assessing DA function are possible, and because there has been little opportunity to examine patients longitudinally or, within cross sectional studies, at the same phase of their illness. Considering these limitations, the fact that cerebrospi'aal fluid (CSF), DA, or homovanillic acid (HVA) levels in schizophrenics and controls generally do not differ is not surprising (Persson and Roos 1969; Gottfries et al 1971; Rimon et al 1971; Bowers 1973, 1974; Post et al 1975; Farley et al 1977; Berger et al

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1980; Gattaz et al 1982). In one study, Lindstrom (1985) found that schizophrenics had lower CSF HVA levels compared to controls, and that HVA levels were directly correlated with social interest and inversely correlated with lassitude and slow movements. Others have also found that decreased CSF HVA levels may be associated with a poor prognosis (Bowers 1974). Thus, lower levels of DA function have been linked to negative symptoms. Transient increases in plasma HVA levels have been correlated with the severity of psychotic symptoms during acute relapse (Davis et al 1985). Further, plasma HVA levels faU as psychosis remits in response to neuroleptic treatment (Pickar et al 1986). Thus~ this measure of DA activity fluctuates during the course of schizophrenia, being lower during residual phases when negative symptoms are usually more prominent, and higher during periods of psychotic exacerbation. Postmortem studies of DA concentrations or tu~over in schizophrenic brain may be of little use in testing our hypothesis as there is no ability to preselect the state of the patient at the time of death, and stressful agonal events are likely to produce spurious changes in such DA measures. Nonetheless, there have been three studies in which increased concentrations of DA were found. Bird et al (1979) found increased concentrations of DA in the nucleus accumbens and anterior perforated substance in brains from schizophrenics compared to controls, No difference was found in other brain areas containing DA (i.e., putamen, caudate, septum, and amygdala [central nu'leus]). While these findings might have been caused by prior neuroleptic treatment, such an artifact seems inconsistent with the observed regional specificity. Crow et al (I979) also found increased DA concentrations in basal forebrain structures of schizophrenic brain, but in this case the difference was restricted to the caudate. No difference in HVA concentrations in any brain area between the groups was found. The apparent discrepancy between the findings of Bird et al and Crow et al may be explained by differences in dissection technique; it has been pointed out that nucleus accumbens may have been included within the caudate samples in Crow's study (Bird et al 1979). Reynolds (1983) also found increased concentrations of DA in the amygdala of postmortem schizophrenic brain, as well as a left-to-right asymmetry (left was higher). The strong correlation between antipsychotic potency and DA D2-receptor affinity among neuroleptics suggested early on that there might be DA D2-receptor abnormalities in schizophrenic brain (see Seeman 1980 for review). Postmortem measurements of DA D2 receptors in caudate nucleus, putamen, and nucleus accumbens of postmortem brain have consistently revealed increased receptor density values in schizophrenics compared to normals (Lee et al 1978; Owen et ai 1978; Lee and Seeman 1980; Cross et al 1981). This finding is highly compatible with our hypothesis. However, some have suggested that this difference is due to chronic neuroleptic treatment (Mackay et al 1980, 1982), which is well-known to increase DA D2-receptor densities in animats (see Seeman 1980 lbr review). Creese and Hess (1986) have reported that DA Dl-receptor density values are decreased in the face of increased DA D2-receptor density values in schizophrenic brain, a dissociation not easily explained as the result of neuroleptic treatment. Further, DA D2-receptor density values in the brain of schizophrenics have a bimodal distribution not attributable to differences in neuroleptic exposure (Seeman et al 1984, 1987). Studies of basal ganglia DA D2-receptor density using positron emission tomography (PET) in living schizophrenic patients known to be neuroleptic naive have yielded conflicting results. Wong et al (1986), using a spiperone derivative as a label, found approximately twofold elevations in DA D2-receptor densities in a small group of drugnaive American patients. Farde et al (1987, 1990), using labeled raclopride, found no

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difference in similarly small groups of Swedish drag-naive patients and controls. This difference might be',accounted for by differences in the patient samples. However, Seeman et al (1990), have recently reported that the use of raclopride for PET studies underestimates DA D2-receptor densities, and would obscure group differences, due to the ability of endogenous tissue DA to displace this radioligand. Fu,~hennore, raclopride labeling of DA D2 receptors in mesolimbic areas would be confounded by the presence of 12A D3-receptor binding sites (Sokoloff et al 1990). Finally, a recent study of brain blood flow assessed by injections of H2~50 followed by PET scanning I~as offered evidence of an asymmetric subcortical abnormality in schizophrenic patients. Early et al (1987) found increased H21-~O uptake (i.e., increased blood flow) in the left globus pallidum of 10 schizophrenic patients compared to 20 controls. These investigators suggest that such an alteration in blood flow could be caused by increases in the firing rate of nucleus accumbens or caudate neurons that project to the pallidum, a pattern consistent with decreases in mesolimbic DA transmission and our hypothesis. While this important finding awaits replication by other groups, techniques of in vivo assessment such as this one may present the most promising avenue to advance the field by studying longitudinal changes in subcortical function in schizophreniic patients. Summary The purpose of this paper has been to prepose a specific hypothesis to explain the pathogenesis of schizophrenia. It was suggested nearly 20 years ago that the pathogenesis of schizophrenia was embodied in the limbic system and its interconnections with mesolimbic DA projections (Stevens 1973). Today, the techniques are becoming available to pursue this hypothesis. We feel that our hypothesis offers advantages in that it proposes a specific, testable mechanism that explains how increased mesolimbic DA transmission could become coupled to chronic abnormalities of limbic function. Based on animal experiments that link behavioral inhibition with activation of a limbic loop circuit, the negative and positive phases of schizophrenia can be explained by changing levels of mesolimbic DA input to this circuit. The neurochemical literature in schizophrenia research, although conflicting to some degree, is most consistent with our hypothesis, rather than hypotheses based on constant increases or decreases in subcortical DA function. This model can be further tested in animals using the hippocampal kindling paradigm as well as other approaches. As in vivo imaging methodologies continue to develop, state-specific longitudinal studies should be performed in schizophrenia patients. We may eventually find that our hypothesis applies to only certain patients with schizophrenia, or to a particular period of the illness (i.e., first 5 years). Alternative mechanisms that give greater attention to lesion phenomena, intrinsic abnormalities of DA adaptation, other neurotransmitters (e.g,, serotonin), or other brain areas (Carlsson 1988; Friedhoff 1988; Luchins 1990; Weinberger 1987) may pertain better to other circumstances.

Thisworkwas supportedin part by a specialgrantof the MedicalResearchServiceofthe VeteransAdministration (now Departmentof VeteransAffairs)to the Schizopl~'eniaBiologicResearchCenter(SBRC)at the Palo Alto VA Medical Center, and by grant MH30854 to the VA StanfordMental Health Clinical ResearchCenter at Stanford University.The authorsthat& PamelaJ. Elliottfor manuscriptpreparationand editorialadvice.

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