REVIEW

A Neurobiological Basis for Substance AbuseComorbidity in Schizophrenia

R. Andrew Chambers, John H. Krystal, and David W. Self

It is commonly held that substance use comorbidity inschizophrenia represents self-medication, an attempt bypatients to alleviate adverse positive and negative symp-toms, cognitive impairment, or medication side effects.However, recent advances suggest that increased vulner-ability to addictive behavior may reflect the impact of theneuropathology of schizophrenia on the neural circuitrymediating drug reward and reinforcement. We hypothesizethat abnormalities in the hippocampal formation andfrontal cortex facilitate the positive reinforcing effects ofdrug reward and reduce inhibitory control over drug-seeking behavior. In this model, disturbances in drugreward are mediated, in part, by dysregulated neuralintegration of dopamine and glutamate signaling in thenucleus accumbens resulting form frontal cortical andhippocampal dysfunction. Altered integration of thesesignals would produce neural and motivational changessimilar to long-term substance abuse but without thenecessity of prior drug exposure. Thus, schizophrenicpatients may have a predilection for addictive behavior asa primary disease symptom in parallel to, and in manycases independent from, their other symptoms.Biol Psy-chiatry 2001;50:71–83 ©2001 Society of BiologicalPsychiatry

Key Words: Schizophrenia, substance abuse, depen-dence, dual diagnosis, dopamine, nucleus accumbens,hippocampus

Introduction

Substance disorder comorbidity, although common inmany psychiatric illnesses, is particularly prevalent in

schizophrenic populations (Selzer and Lieberman 1993).Results from the Epidemiologic Catchment Area (ECA)study show that schizophrenia ranks second only toantisocial personality disorder (which included substanceabuse criterion at the time) in rates of substance abusecomorbidity (Reigier et al 1990). These ECA data also

found that patients with schizophrenia are 4.6 times morelikely to have substance use disorders than persons with-out mental illness (3 times higher for alcohol, 6 timeshigher for other illicit drugs). Schizophrenic populationscommonly use one or more of several substances, includ-ing nicotine, alcohol, cannabis, cocaine, and amphet-amines (Cuffel 1992; Dixon et al 1991; Mueser et al 1990;Schottenfeld et al 1993; Selzer and Lieberman 1993;Zisook et al 1992). Nicotine is clearly the most highlyself-administered drug in schizophrenic populations, withuse rates ranging from 70 to 90%, compared with 26% inthe general population (Buckley 1998; Giovino et al 1994;Hughes et al 1986; Masterson and O’Shea 1984; O’Farrellet al 1983). In independent populations of patients withschizophrenia, lifetime prevalence of cocaine abuse ordependence ranges from 15 to 50%; amphetamine abusefrom 2 to 25%, alcohol abuse from 20 to 60%, andcannabis abuse from 12 to 42% (Buckley 1998; DeQuardoet al 1994; Mueser et al 1990; Strakowski et al 1994).

Apart from socioeconomic and demographic factors, themost widely held explanation for substance use comorbid-ity in schizophrenia and other mental illnesses is theself-medication hypothesis (Buckley 1998; Dalack et al1998; Krystal et al 1999). This hypothesis is based on thepsychologic construct of negative reinforcement, definedhere as the reinforcing property associated with the “pur-poseful removal of an aversive stimulus” (March 1999).Self-medication hypotheses assert that patients use drugsto alleviate aversive disease symptoms or medication sideeffects; however, a growing body of evidence suggeststhat the neuropathology of schizophrenia may contributeto the vulnerability to addiction by facilitating neuralsubstrates that mediate positive reinforcement. This primaryaddiction hypothesis is based on basic and clinical neuro-science literature that supports two fundamental tenets:

1. The putative neuropathology underlying schizophre-nia involves alterations in neuroanatomic circuitrythat regulate positive reinforcement, incentive moti-vation, behavioral inhibition, and addictive behavior.

2. Experimental interventions that model neuropatho-logic and behavioral aspects of schizophrenia inanimals also facilitate positive reinforcement andthe incentive motivational effects of reward-relatedstimuli.

From the Ribicoff Research Facilities, West Haven Veterans AdministrationHospital, and the Connecticut Mental Health Center (RAC), Department ofPsychiatry, Yale University School of Medicine, New Haven (RAC, JHK,DWS) Connecticut.

Address reprint requests to R. Andrew Chambers, M.D., Abraham RibicoffResearch Facilities, 3rd Floor, Room 331, Connecticut Mental Health Center,34 Park Street, New Haven, CT 06508.

Received December 1, 2000; revised February 12, 2001; accepted February 25,2001.

© 2001 Society of Biological Psychiatry 0006-3223/01/$20.00PII S0006-3223(01)01134-9

An inherent feature of this hypothesis is that both theschizophrenia syndrome and vulnerability to addiction areprimary disease symptoms, each directly caused by com-mon neuropathologic substrates (Figure 1). In contrast, theself-medication hypothesis asserts that vulnerability toaddiction is a reaction to the schizophrenia syndrome ormedication side effects, and thus represents a secondarysymptom. In this scenario, drug use isdependenton theexperience or manifestation of symptoms; however, theprimary addiction hypothesis posits that both schizophre-nia symptoms and addictive behavior occur asindepen-dentmanifestations of the same disease. This latter featuremay account for the failure to find a consistent associationof drug addictions with alleviation of general or specificsymptoms in schizophrenia as described below.

First, several studies indicate that substance use rates inschizophrenic populations are substantially higher whencompared with other psychiatric populations who wouldbe as likely to self-medicate. For example, althoughsmoking is suggested to alleviate negative emotionalstates, anxiety, depression, or poor cognitive functioning,nicotine use in patients with schizophrenia is more prev-alent than in nonschizophrenic patients who exhibit simi-lar symptomatology as primary features of their disorders.Tobacco use is consistently reported in more than 70% ofschizophrenic patients but in less than half of patients withmajor depression, anxiety disorders, panic disorders, andpersonality disorders (Glassman et al 1992; Hughes et al1986; Pohl et al 1992). Even when considering theconstellation of symptomsin schizophrenia,there is noconsensus among studies for substance use comorbidity tobe associated with any particular subset of symptoms inindividual patients (Cuffel et al 1993; DeQuardo et al1994; Lambert et al 1997; Van Ammers et al 1997).Instead, studies on large patient populations find that drugavailability is a primary determinant for the type of drugspatients use (Baigent et al 1995; Lambert et al 1997).

These findings may suggest an association between heter-ogeneous schizophrenia presentations and a facilitation ofthe positive reinforcing and incentive motivational prop-erties of addictive drugs.

A second consideration is that drugs of abuse have acomplex array of effects in schizophrenic patients, oftenproducing outcomes that are inconsistent with the viewthat these drugs serve to medicate their symptoms. Forexample, although some patients report symptom reliefwith drug use, others report symptom exacerbation, andyet their drug use persists (Addington and Duchak 1997;Selzer and Lieberman 1993). In many cases, self-reportsof symptom improvement with drug use are contradictoryto concurrent objective clinical observations that clearlyshow symptom exacerbation (DeQuardo et al 1994; Seibylet al 1993). Moreover, drug or alcohol use greatly in-creases the likelihood of rehospitalization, length of hos-pitalization, need for greater neuroleptic dosage, andtreatment noncompliance in schizophrenic patients (Dixon1999; Gerding et al 1999; Seibyl et al 1993). Interestingly,the termself-medicationis commonly used to explain highrates of drug use in dual-diagnosis patients who areespecially medication noncompliant (Agarwal et al 1998;Seibyl et al 1993). These data suggest that similar to thenatural course of addictions in nonschizophrenic patients,the incentive motivational properties of drugs that producechronic drug taking in schizophrenia outweigh motivationto abstain stemming from psychiatric, medical, and finan-cial consequences of drug use.

Another observation indicating a dissociation of schizo-phrenia symptomatology from addictive behavior is theprevalence of substance abuse before clinical presentationand medication treatment in schizophrenic patients. Stud-ies have found that both drug and alcohol abuse occursbefore the onset of psychosis and neuroleptic treatment in14 to 69% of cases of schizophrenia (Berti 1994; Buckley1998). One study found that 77% of first-episode patientsare already smokers before treatment (McEvoy and Brown1999). In another study, smoking rates are 54% and 15%in early- versus late-onset schizophrenia respectively,despite a similar duration of neuroleptic treatment (Sandykand Awerbuch 1993). Although it is difficult to distinguishthe initiation of drug use from the onset of prodromalsymptoms, in many cases addiction vulnerability mayoccur as a natural antecedent to onset of other frank signsand symptoms, as a primary consequence of neuropatho-logic brain development that will later present asschizophrenia.

A final limitation of attributing drug abuse to self-medication of symptomatology is the assignment of treat-ment value to the effects unique to each type of abuseddrug while overlooking their common ability to mediatepositive reinforcement. Different drugs commonly abused

Figure 1. The self-medication hypothesis suggests that sub-stance abuse comorbidity is a secondary reaction to primaryschizophrenia symptoms, representing a negative reinforcementmodel of symptom alleviation. The primary addiction hypothesissuggests that propensity for drug addiction is itself a primarysymptom in schizophrenia directly resulting from neuropatho-logic processes that facilitate positive reinforcement, increasingthe motivational and behavioral responses to addictive drugs.

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by schizophrenic patients produce highly specific effectson mood, perception, and cognitive functioning, and evenmutually opposing subjective experiences via activity on agreat diversity of neurotransmitter systems (Ling et al1996). These facts have lead to attempts to define inde-pendent neurobiological mechanisms for self-medicationspecific to each drug of abuse in association with aparticular psychiatric symptom, resulting in a host ofrelatively disparate theories that are not generalizable tomore than one drug. Furthermore, these theories do notexplain why standard medication treatments, with well-known efficacy for a variety of symptoms in schizophre-nia, are not alone generally effective in reducing substanceabuse in dual diagnosis cases (Selzer and Lieberman1993). The primary addiction hypothesis focuses on thecommon ability of the abused drugs to produce incentive-motivation and positive reinforcement while remainingunencumbered by their differential ability to worsen orameliorate certain symptoms of schizophrenia. A patho-logic facilitation of incentive-motivational processes isconsistent with observations that schizophrenic patientsare known to suffer from a variety of apparently “sense-less” motivational disturbances in parallel to substanceabuse. These include motor and behavioral stereotypies,frequent and inappropriate masturbation, polydipsia, bu-limia, pacing, pica, hoarding, and pathologic gambling(Aizengerg et al 1995; Chambers and Potenza 2001;Luchins 1992; Skopec et al 1976).

The primary addiction hypothesis offers a parsimoniousexplanation for substance use comorbidity in schizophre-nia by viewing addiction as an independent processstemming directly from a common neuropathologic root.The hypothesis is synthesized from basic neuroscienceliterature suggesting that neurodevelopmental alterationsin schizophrenia overlay precisely on neural substratesthat regulate addictive behavior. We describe the funda-mental neurocircuitry implicated in both schizophreniaand addiction and how neurodevelopmental alterationscould disrupt normal signal integration within these cir-cuits. Experimental manipulation of key components inthis circuitry is shown to directly facilitate brain substratesthat mediate positive reinforcement and to impair mecha-nisms that exert inhibitory control over addictive behavior.

Common Neurocircuitry Implicated in BothAddiction and Schizophrenia

Involvement of the Mesolimbic Dopamine System inAddiction and Schizophrenia

Most drugs abused by humans also are self-administeredby laboratory animals. A substantial literature has estab-lished the mesolimbic dopamine system as a major neuralsubstrate for the reinforcing effects of psychostimulants,

ethanol, nicotine, and cannabinoids in animals (Fibiger etal 1992; Koob 1992; Wise 1990). This system consists ofdopamine (DA) neurons in the ventral tegmental area(VTA) and their target neurons in forebrain regions suchas the nucleus accumbens (NAc). Rats will self-administerDA, amphetamine (which releases DA), and cocaine(which elevates DA levels by blocking reuptake), all directlyinto the NAc, suggesting that DA receptors in the NAcmediate reinforcing stimuli (Carlezon et al 1995; Dworkin etal 1986; Hoebel et al 1983). Other drugs used by schizo-phrenic patients, such as ethanol, nicotine, and cannabinoids,also cause increased DA release in the NAc, possibly throughdisinhibition of VTA DA neurons (Chen et al 1990; Imperatoand Di Chiara 1986; Tanda et al 1997). These findingshave led investigators to suggest that DA release in theNAc is a final common mechanism for the reinforcingeffects of psychostimulants and other abused drugs(Bozarth and Wise 1986; Di Chiara and Imperato 1988).

The mesolimbic DA system also may be involved inmediating drug craving. This hypothesis is based on thefact that stimuli that induce relapse in animal models anddrug craving in human studies are all known to increaseDA levels in the NAc (Ito et al 2000; Self 1998; Stewart2000). These stimuli include small priming doses of drugs,stress, and drug-associated cues. In humans, craving forcocaine, nicotine, and ethanol also is induced by druglikeDA agonists (Haney et al 1998; Jaffe et al 1989). Incontrast, DA receptor antagonists fail to induce heroin- orcocaine-seeking behavior (Shaham and Stewart 1996;Weissenborn et al 1996), despite their ability to producewithdrawal-like aversive consequences (Shippenberg andHertz 1987). Moreover, although several studies suggestthat drug withdrawal is associated with hypofunction inDA reward substrates, these changes actually are associ-ated with anhedonia rather than increased drug-seekingbehavior (Koob and Le Moal 1997). Together these studiessupport the idea that drug craving is induced by stimulithat facilitate, rather than depress, DA reward systems.

The mesolimbic DA system also pertains to schizophre-nia, based on the classic findings that 1) typical neurolep-tics exert antipsychotic activity via blockade of DAreceptors; and 2) psychostimulants elevate DA levels inthe NAc, causing psychotic symptoms in both “healthy”subjects and schizophrenic patients (Crow et al 1977;Lieberman et al 1990). Contemporary revisions of thedopamine hypothesis suggest that schizophrenia symp-toms emerge from a functional hyperactivity of DAneurons projecting to the NAc, associated with functionalhypoactivity of DA neurons projecting to the frontalcortex (Davis et al 1991; Deutch 1993; Goldstein andDeutch 1992). Other revisions suggest that psychosis andthought disorder may result, in part, from a state ofabnormal glutamatergic cortical activity associated with

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exaggerated DA release or dysregulated DA signaling inthe NAc (Csernansky and Bardgett 1998). This imbalanceof cortical and DA signaling may contribute to impropergating of perceptual and thought processes (Hoffman andMcGlashan 1993; Weinberger et al 1994).

The primary addiction hypothesis incorporates evidenceof hyperactivity in NAc DA signaling as it relates both topsychotic symptoms and addictive behavior. The ability oftypical antipsychotics to attenuate behavioral sensitizationand reinforcement produced by psychostimulants agreeswith this idea (Glenthoj et al 1993; Richardson et al 1994;Roberts and Vickers 1987). In rats, an imbalance favoringsubcortical over cortical DA signaling, whether biologi-cally inherent or experimentally induced, increases sensi-tivity to the reinforcing effects of psychostimulants(McGregor et al 1996; Piazza et al 1991; Schenk et al1991). Stress also activates the mesolimbic DA system andis known to exacerbate psychotic symptoms, stimulatedrug craving in human drug abusers, and induce drug-seeking behavior in animals (Lieberman et al 1990; Sinhaet al 1999; Stewart 2000; Walker and Diforio 1997). It ispossible that an imbalance of cortical-subcortical DA con-tributes to stress-induced exacerbation of psychosis and drugseeking in patients with schizophrenia. In this regard, thesubset of NAc neurons responsive to stress are also thoughtto be a primary locus of antipsychotic activity (Deutch 1993).

Dysregulation in Cortical, Temporal Limbic, andMesoaccumbens Circuits Is Implicated in BothSchizophrenia and Substance Abuse Disorders

Although functional hyperactivity in the mesolimbic DAsystem may be involved in both schizophrenia and addic-tive behavior, it is important to consider neuropathology ina larger neural network that integrates mesolimbic DA inthe NAc with cortical and hippocampal inputs. The inte-gration of these circuits occurs at the level of individualmedium spiny neurons in the NAc, which receive conver-gent excitatory input from the prefrontal cortex (PfC) andthe hippocampal formation and DA input from the VTA.Integration of these signals in NAc neurons is thought tocontribute substantially to the motivational consequenceof drugs or drug-related stimuli. If so, dysfunctionalintegration of cortical, hippocampal, and DA signals inschizophrenic patients could significantly alter their pro-pensity for addictive behavior.

Network dysregulation in schizophrenia may act simi-larly to the network dysregulation in drug addiction.Jentsch and Taylor (1999) suggested that chronic drugexposure produces pathophysiologic changes that contrib-ute to loss of cortical control over DA-mediated behavior.This loss of cortical control is thought to sensitize animalsto the incentive-motivational effects of drugs, contributing

to compulsive drug self-administration (Jentsch and Tay-lor 1999). Other evidence suggests that chronic, drug-induced neuroadaptations in DA receptor signal transduc-tion in the NAc could alter the impact of DA signals fromthe VTA and glutamate signals from the PfC and hip-pocampus (Self 1998; Self and Nestler 1998; White andKalivas 1998). Interestingly, drug-induced changes in-clude decreases in inhibitory G proteins in the NAc,changes that also have been found in postmortem NActissue from schizophrenic patients (Sumiyoshi et al 1995;Yang et al 1998). Notably, decreases in inhibitory Gproteins in the NAc have been found to produce escalationin cocaine self-administration in rats (Self et al 1994) andwould expectedly produce a similar escalation of drug usein schizophrenic patients.

The primary neuropathology in schizophrenia remainsunknown, but current theories are focused on neurodevel-opmental abnormalities in cortical and temporal-limbicstructures, particularly the hippocampal formation and thePfC (Bunney and Bunney 2000; Selemon and Goldman-Rakic 1999; Weinberger et al 1994). The hippocampusdevelops over a longer period than any other forebrainstructure, and its cell migration paths are long, complex,and particularly vulnerable to genetic or environmentaldisturbances during the second trimester of gestation(Scheibel and Conrad 1993). Postmortem tissue fromschizophrenic patients shows a disruption in the laminardistribution of cells in the CA1-CA3 subfields of thehippocampus (Scheibel and Conrad 1993). In addition,hippocampal neurons have decreased soma size in schizo-phrenic patients (Arnold et al 1995). Histopathologicabnormalities are corroborated by neuroimaging showingreductions in hippocampal-amygdaloid volume, concomi-tant with increased lateral ventricular volume, and propor-tional to severity of symptoms (Bogarts et al 1993).Importantly, these abnormalities are localized to hip-pocampal regions that are thought to normally provideexcitatory input to the PfC and frontal subcortical struc-tures. The resultant dysfunctional circuitry may contributeto a decrement in frontal cortical functioning and effec-tiveness during executive tasking, as well as a relativehyperactivity of DA function in the NAc correlating withthe onset of psychosis (Weinberger and Lipska 1995).Thus, clinical manifestation of these hippocampal abnor-malities are thought to become evident after frontal corti-cal and associated subcortical structures undergo finalmaturation during and after adolescence (Goldman-Rakic1994). The validity of this neurodevelopmental theory issupported in rat studies, where postnatal ventral hip-pocampal damage produces hypersensitivity to amphet-amine-induced locomotion but emergent only after ado-lescence (Lipska et al 1993).

Figure 2 illustrates how developmental abnormalities in

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hippocampal and PfC projections to the NAc may contributeto an overall functional hyperresponsiveness to mesoaccum-bens DA release by reducing cortical and hippocampalregulation over DA-mediated responses in schizophrenia(Weinberger and Lipska 1995). This disinhibition ofsubcortical DA systems would parallel theories of reducedcortico-striatal tone associated with drug addiction(Jentsch and Taylor 1999; Volkow and Fowler 2000).

Abnormal input from cortical and hippocampal sourcesmay cause identifiable changes in markers of DA signal-ing in the ventral striatum. For instance, amphetaminechallenge in schizophrenic patients produces abnormallyelevated DA release as marked by heightened displace-ment of radiotracer from D2 receptors in the striatum(Abi-Dargham et al 1998). Attempts to identify postsyn-aptic alterations consistent with a functional DA supersen-sitivity, have been conducted by measurement of striatalD2 receptor densities in living or postmortem brains ofschizophrenic patients. A series of these studies variouslyshows increases, decreases, or no changes, perhaps as aresult of variability in patient subgroups, including largedifferences in neuroleptic exposure (Farde 1997; Haney etal 1998, 1999; Joyce et al 1988; Laruelle 1998; Nordstrom1995; Martinot et al 1994). The possibility that schizo-phrenia is associated with changes in striatal D2 receptor

density is notable in light of human and animal studiessuggesting that D2 receptors are primarily involved indrug craving (DeVries et al 1999; Self et al 1996; Wise1990). In this vein, Seeman has described evidence thatthe ratio of D2 receptor densities to D1 receptors isincreased in the striatum of drug-naive schizophrenicpatients (Seeman et al 1989) and has shown that deficits inthe normal coupling of intracellular elements common toD1 and D2 receptors (Seeman and Nitznik 1990). BecauseD1 receptors are implicated in opposing the drug-seekingeffects of D2 receptor agonists (Self et al 1996), anincrease in the D2/D1 ratio or disruption in D2-D1coupling may be associated with increased vulnerability todrug addiction.

A Neurophysiologic Basis for Vulnerabilityto Addiction in Schizophrenia: In VivoStudies of the Role of the HippocampalFormation in Modulating NucleusAccumbens-Mediated Responses

Anatomy and Neurochemistry of Hippocampal-NAcConnections

The ventral-proximal subiculum (a major output structureof the hippocampal formation) and the CA1 region of the

Figure 2. (A) The neural network implicated in reward, drug addiction, and schizophrenia. Excitatory afferents to the nucleusaccumbens (NAc) from the hippocampal formation relay contextual information relevant to reward and motivation. Excitatory afferentsfrom the prefrontal cortex (PfC) relay command and inhibitory information to the NAc relevant to regulation of thought and motivation.In the NAc, glutamatergic afferents from hippocampal formation and the PfC interact with dopaminergic afferents from the ventraltegmental area (VTA) to regulate motivational processes.(B) In both schizophrenia and drug addiction, a functional disorganizationof afferent excitatory communication to the NAc contributes to relative hyperresponsivity to dopaminergic input from the VTA,increasing motivational salience of drugs and drug-related stimuli. In schizophrenia, dysregulation of hippocampal outputs may disruptPfC communication to the NAc, weakening executive-inhibitory influence on motivational processes by reducing the impact of PfCinputs (gating), reducing excitatory drive of PfC-NAc projections, or both. Dopamine, black arrow; glutamate, striped arrow.

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hippocampus send direct projections to the NAc in atopographically organized manner (Groenewegen et al1987; Kelley and Domesick 1982; Naber and Witter1998). These hippocampal-subicular axons pass throughthe fimbria-fornix and diffusely innervate the entire ante-rior-posterior extent of the NAc (Kelley and Domesick1982). Hippocampal and VTA DA axons form synapses inclose proximity on medium spiny neurons of the NAc,suggesting that physiologic interactions occur at the levelof individual dendrites (Sesack and Pickel 1990; Totterdelland Smith 1989).

Hippocampal inputs to NAc release the neurotransmit-ter glutamate, which acts on postsynaptic NAc neurons,but hippocampal activity also can modulate DA release inthe NAc through both “direct” and “indirect” pathways.The direct pathway involves local modulation of DAterminals by hippocampal-subicular afferents to the NAc(Blaha et al 1997). The indirect pathway involves subic-ular outputs to other brain regions that excite VTA DAneurons and subsequently stimulate DA release in the NAc(Legault et al 2000; Legault and Wise 1999). This latterpathway may involve hippocampal-subicular projectionsto the PfC or ventral pallidal neurons, which in turn projectto the VTA (Legault et al 2000; Todd and Grace 1999). Inany event, hippocampal modulation of NAc neuronsapparently involves convergent modulation of both gluta-matergic and dopaminergic signaling.

Integration of DA and Glutamatergic Signals inNAc Neurons

Nucleus accumbens neurons are excited by direct mono-synaptic projections from several distal brain regions,including the PfC, amygdala, thalamus, entorhinal cortex,and the subiculum-CA1 region of hippocampal formation(Finch 1996; Lopes da Silva et al 1984; O’Donnell andGrace 1995; Pennartz et al 1994). Excitatory inputs fromup to five of these distal regions may converge on a singleNAc neuron, resulting in unique spatial-temporal patternsof activity (Finch 1996). For example, concurrent stimu-lation of the PfC and hippocampal formation producesadditive responses in a subset of NAc cells, whereas otherunique responses are produced by concurrent stimulationof amygdalar and hippocampal inputs (Finch 1996). Pen-nartz et al (1994) proposed that specific ensembles ofneurons in the NAc perform computations that representvarious motivational states. These ensembles receive dis-tinct combinations of convergent information from thehippocampus, PfC, amygdala, and VTA; altered firingpatterns in these ensembles are thought to determinebehavioral output relating to premotor planning or moti-vation state (Pennartz et al 1994). Building on thisframework, O’Donnell et al (1999) proposed that hip-

pocampal afferents convey spatial information, whereasamygdalar afferents convey emotional information, bothof which ultimately interact to gate activity in ventral-striatal-thalamo-prefrontal-cortical circuits. These ventral-striatal-thalamo-prefrontal-cortical circuits are hypothe-sized to regulate ordered thought and motivational stateanalogous to the dorsal striatal system, where striatal-thalalmo-cortical circuits are thought to direct orderedmovement (Cummings 1993; Groenewegen et al 1997).

The hippocampal inputs to the NAc are of particularimportance because they function by gating inputs fromother brain regions such as amygdala and PFC (O’Donnelland Grace 1995). For example, NAc neurons display threegeneral patterns of baseline activity: 1) silent, 2) sponta-neously firing at low constant rates, or 3) one of twobistable membrane potentials, one of which exhibits a highrate of spontaneous firing (O’Donnell and Grace 1995).Activation of hippocampal afferents—but not cortical,amygdaloid, or thalamic afferents—induces bistable cellsto move to the depolarized or active state. Stimulation ofPfC inputs to the NAc fails to alter firing of NAc neuronsunless they are facilitated by intact hippocampal input,indicating that hippocampal input gates information flowthrough cortico-ventral-striatal projections (O’Donnell etal 1999; O’Donnell and Grace 1995). Other work suggeststhat hippocampal input also influences neuroplasticity inNAc neurons. For example, tetanizing stimulation of thefimbria-fornix pathway results in long-term potentiation inNAc neurons but causes long-term depression in NAcneurons receiving concurrent input from the basolateralamygdala (Mulder et al 1998). Therefore, developmentalneuropathology in hippocampal function in schizophreniawould produce profound disruption of these gating andneuroplastic processes.

Dopamine generally acts to dampen the excitatoryresponse to cortical and hippocampal afferents in NAcneurons (O’Donnell and Grace 1994; O’Donnell andGrace 1996; O’Donnell et al 1999; Yang and Mogenson1984). Importantly, this effect would allow fewer bistableNAc neurons to enter the depolarized or active state,thereby reducing the influence of PfC afferents(O’Donnell et al 1999). In the PfC, phasic DA release alsocan dampen PfC output to the NAc by rendering PfCneurons less responsive to excitatory stimulation from thehippocampal formation (Jay et al 1995). Therefore, a DAflux can act via at least three different mechanisms to takeNAc neurons “off-line” from prefrontal executive modu-lation: 1) reducing activity in PfC-NAc afferents, 2)reducing NAc and PfC responsiviness to hippocampalinput, and 3) reducing NAc responsiveness to PfC input.Together these DA effects could reduce inhibitory controlover reward-seeking and other DA-mediated behaviors.This idea is supported by a vast neuropsychiatric literature

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that describes behavioral disinhibition following frontallobe injuries in humans (Cummings 1993). A loss ofinhibitory control over DA-mediated behaviors may inturn contribute to both schizophrenia and addictive symp-tomatology. Interestingly, the dampening effect of DA oncortical and hippocampal inputs to the NAc is mediatedprimarily by D2 receptors, which are implicated both inexacerbation of psychotic symptoms and in compulsivedrug-seeking behavior associated with hyperactivaton ofthe DA system (DeVries et al 1999; O’Donnell and Grace1994; Self et al 1996; Sunahara et al 1993).

The Hippocampus Modulates NAc-MediatedBehaviors Associated with Schizophrenia andSubstance Abuse

Pharmacologic or surgical compromise of hippocampalfunction can produce animal behavior consistent with arelative “hyperdopaminergic state” in mesolimbic DApathways that mimics certain features of the schizophreniasyndrome (Lieberman et al 1990; Lillrank et al 1995;Lipska et al 1992; Reinstein et al 1982; Schaub et al 1997;Whishaw and Mittleman 1991; Wilkinson et al 1993).Notably, lesions of the hippocampus in animals canproduce hypersensitivity to dopaminergic stimulation thatis greater than that produced by lesions of the PfC or theamygdala, consistent with the hierarchical dominance ofhippocampal over PfC and amygdalar inputs to the NAc(Schaub et al 1997). Moreover, the impact on DA-mediated behavior corresponds to the extent of the lesionand is greater with comprehensive lesions of multiplehippocampal substructures (Mittleman et al 1998).

Adult rats with lesions of the hippocampal formationalso exhibit greater NAc DA release when exposed toconditioned stimuli associated with foot-shock stress,consistent with a hyperdopaminergic state (Saul’skaya andGorbachevskaya 1998); however, neonatal hippocampallesions produce hyperlocomotion to stress and amphet-amine, without altering stress- and amphetamine-inducedDA release in the NAc (Brake et al 1999; Lillrank et al1999). This latter effect may represent an acquiredpostsynaptic or neural network hypersensitivity to NAcDA responses, resulting from disruption of hippocampal-cortical inputs during postnatal maturation (Brake et al1999; Lillrank et al 1999). Neurodevelopmental hip-pocampal abnormalities underlying schizophrenia couldtherefore sensitize DA responses at the level of NAcneuronal ensembles, which may mimic sensitization in DAsystems that occurs with repeated drug exposure, increas-ing vulnerability to drug addiction (Jentsch and Taylor1999; Self and Nestler 1998; White and Kalivas 1998).Interestingly, acute activation of the CA1 region of thehippocampus and subiculum also increases locomotor

behavior and DA release in the NAc, possibly via hip-pocampal regulation of VTA cell firing as discussedearlier (Brudzynski and Gibson 1997; Legault et al 2000;Ma et al 1996). Together these results suggest thatalthough acute activation of the intact hippocampus canproduce phasic DA release in the NAc, permanent hip-pocampal lesions also increase the relative effects ofdopaminergic activity on NAc neuronal ensembles. Also,the degree to which this relative dopaminergic effect maybe detected as changes in markers of DA function maydepend on the developmental stage at the time of thehippocampal insult.

An important behavioral parameter associated with DAsystem functioning in humans and animals and withcognitive gating deficits in schizophrenia is the disruptionof latent inhibition (LI). Normal LI refers to the ability ofa stimulus preexposure, before Pavlovian conditioning, toweaken the subsequent association of the stimulus withsalient events. Persons with acute, unmedicated psychosisor normal subjects administered dopaminergic psycho-stimulants both show a reduced capacity for LI (Baruch etal 1988; Gray et al 1992). Loss of LI in schizophrenia hasbeen interpreted as “an inability to screen out irrelevantstimuli” or a “disruption in the normal ability to use pastcontextual regularities as a guide to current informationprocessing” (Gray et al 1995; Weiner 1990). Notably,patients with schizophrenia treated with typical neurolep-tics show a restoration of LI (Baruch et al 1988). Simi-larly, animals with lesions to the greater hippocampalformation show loss of some forms of LI that is restoredwith haloperidol administration, suggesting hippocampalinvolvement in these forms of inhibitory control overbehavior (Schmajuk et al 2000). Furthermore, the disrup-tion of LI produced by hippocampal lesions is attributed tohyperactivity in the meso-NAc DA system, suggesting thatcertain features of schizophrenia may involve a similarmechanism (Gray et al 1995).

Abnormalities in LI associated with hyperdopaminergicstates may also produce abnormalities in reward-relatedlearning processes. Dopamine neurons normally fire inresponse to novel rewards and diminish firing as rewardsbecome more predictable (Hollerman and Schultz 1998).This transition could be disrupted by a hyperdopaminergicstate produced by dysfunctional cortical-hippocampal in-put to NAc and by drug-induced DA release, leading tocontinuous neural representation of rewards as novel.Thus, in addition to cognitive gating deficits in LI,reward-related learning may be altered by hippocampaldysfunction. Furthermore, lesions of ventral hippocampusin adult rats increase resistance to extinction from foodreinforced behaviors and reduce avoidance of rewardspaired with conditioned fear (Clark et al 1992). These datasuggest that the hippocampus mediates control over be-

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havior associated with inhibitory learning (extinction andconditioned avoidance). In addition, hippocampal lesionsdecrease food neophobia and increase the reinforcingefficacy of sucrose or electrical stimulation of reward path-ways (Burns et al 1996; Kelley and Mittleman 1999;Schmelzeis and Mittleman 1996). Together these behav-ioral findings suggest that hippocampal dysregulation inschizophrenia could enhance the reinforcing efficacy pro-duced by natural and drug rewards by interfering with normalinhibitory control over compulsive reward-seeking behavior.

Summary

This article reviews evidence that developmental neuro-pathology in hippocampal and PfC pathways contributesboth to symptoms of schizophrenia and to vulnerability toaddictive behavior via dysfunctional interactions with theNAc. This hypothesis posits that substance disorder co-morbidity represents an independent primary diseasesymptom in schizophrenia, rather than a form of self-medication secondary to classic schizophrenia symptomsor medication side effects.

The primary addiction hypothesis is based on substan-tial data that directly relates deficits in hippocampal-cortical function with neurochemical, neurophysiologic,and neurobehavioral alterations consistent with a facilita-tion of both schizophrenia and addictive behavior. Figure3A illustrates this hypothesis by showing that hippocam-pal and PfC outputs normally exert inhibitory control overDA-mediated behavior via their interaction with NAcneurons. During this “resting state,” homeostasis betweenhippocampal-cortical inputs and low basal dopaminergictone contribute to stability in neuronal ensembles andsuppression of uncontrolled goal-directed behavior infavor of executive premotor planning. The behaviorally“activated state” is produced by phasic DA surges inresponse to novelty, natural or drug rewards, stressfulsituations, or exposure to salient cues associated withrewards (Figure 3B). These DA surges act in the PfC todampen afferents to the NAc and in the NAc to counteractthe glutamatergic influence of hippocampal and PfC in-puts. The vast majority of NAc output neurons (many ofwhich receive hippocampal and PfC input) send descend-ing GABAergic projections to the ventral globus pallidus

Figure 3. (A) Nucleus accumbens (NAc): “resting state.” Ensembles of GABAergic neurons are regulated by a balance ofglutamatergic afferents from prefrontal cortex (PfC) and other limbic regions and by dopaminergic afferents from the ventral tegmentalarea (VTA). Hippocampal input to the NAc facilitates PfC glutamatergic modulation of NAc neurons while also provoking low basaldopamine (DA) release to maintain stability of neuronal ensembles. This balance provides ongoing inhibitory tone of GABAergicefferents on striatal output structures. In this state, behavioral inhibition is maintained.(B) Nucleus accumbens: “activated state.”During presentation of novel, rewarding, or stressful stimuli or exposure to addictive drugs, DA surges in the NAc and PfC, dampensPfC influence on NAc neurons. This DA surge also attenuates hippocampal input, further diminishing its ability to facilitate PfCmodulation of NAc neurons. Attenuation of PfC tone, coupled with DA surges in the NAc, causes changes in NAc GABAergic outflow,altering neuronal activation of ventral pallidal and thalamic nuclei. In this state, reward-seeking behavior is disinhibited.(C) Inschizophrenia, abnormal hippocampal afferents to the NAc and PfC and hyperfunctioning of DA signals result in a relatively inflexiblemotivation system due to a failure of executive PfC control over NAc neurons. This “relative” hyperfunctioning of DA input isassociated with a baseline that operates closer to the “activated state” (Figure 3B) and is less able to enter a “resting state” (Figure 3A).Such dysregulation may create a lower threshold for DA releasing stimuli to recruit motor output programs, and drug reward-seekingbehavior is disinhibited.

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and other brain-stem structures involved in thalamo-cortical loops that regulate thought, premotor planning,motivation, and movement (Mugnaini and Ortel 1985;Yang and Mogensen 1985). Dopaminergic surges in theNAc could diminish NAc GABAergic outflow to thesestructures, serving to translate motivation into behavioralaction (Lavin and Grace 1994). Thus, DA surge wouldshift NAc function toward activation of motivated behav-ior, either in the form of appetitive (approach) or aversive(withdrawal) responses. In schizophrenia (Figure 3C),developmental alterations in hippocampal and PfC ultra-structure impair the ability of hippocampal projections toprovide excitatory drive of PfC-NAc projections andprovide effective facilitation of PfC inputs to the NAc,resulting in functional hyperresponsiveness to basal anddrug-stimulated DA release. Thus, the patient with schizo-phrenia is particularly sensitive to the reward-activated,relative hyperdopaminergic state induced by addictivedrugs in the NAc, by virtue of reduced inhibitory controlover DA-mediated behavior. Such cortical-hippocampaldysfunction ultimately could lead to perseveration ofdrug-seeking and a propensity for relapse, as well asclassic schizophrenic symptomatology.

This hypothesis integrates both clinical and basic neu-robiological data and offers a comprehensive heuristicframework to direct future investigations on substanceabuse comorbidity in schizophrenia. Its major clinicalimplications include the need to introduce substance abuseeducation and other forms of prevention early in thecourse of treatment. Furthermore, this hypothesis also maysuggest an explanation for dual diagnosis cases in otherpsychiatric disorders thought to involve hippocampal dys-function, including posttraumatic stress disorder, border-line personality disorder, and major affective disorders(Chambers et al 1999). Further studies are needed todetermine whether animal models of hippocampal dys-function in schizophrenia can produce certain core fea-tures of the addicted phenotype, such as escalating drugintake and a propensity for relapse. These studies poten-tially could identify both convergent and divergent mech-anisms for comorbidity between addictive behavior andschizophrenia. A better understanding of these mecha-nisms will inevitably provide the basis for better treatmentstrategies for motivational disturbances that are perva-sively present in the mentally ill.

Support for this work was provided by National Research Service Award,Department of Health and Human Services of the Public Health Service,Veterans Administration Special Neuroscience Research FellowshipTraining Grant, Department of Veteran’s Affairs and Alcohol ResearchCenter, Schizophrenia Biological Research Center, and National Centerfor PTSD (NIAA Grant No. KOZAA00261).

ReferencesAbi-Dargham A, Gil R, Krystal J, et al (1998): Increased striatal

dopamine transmission in schizophrenia: Confirmation in asecond cohort.Am J Psychiatry155:761–767.

Addington J, Duchak V (1997): Reasons for substance use inschizophrenia.Acta Psychiatr Scand96:329–333.

Agarwal MR, Sharma VK, Kishore Kumar KV, Lowe D (1998):Non-compliance with treatment in patients suffering fromschizophrenia: A study to evaluate possible contributingfactors.Int J Soc Psychiatry44:92–106.

Aizengerg D, Zemishlany Z, Dorfman-Etrog P, Weizman A(1995): Sexual dysfunction in male schizophrenic patients.J Clin Psychiatry56:137–141.

Arnold SE, Franz BR, Gur RC, et al (1995): Smaller neuron sizein hippocampal subfields that mediate cortical-hippocampalinteractions.Am J Psychiatry152:738–748.

Baigent M, Holme G, Hafner RJ (1995): Self-reports of theinteraction between substance abuse and schizophrenia.AustN Z J Psychiatry29:69–74.

Baruch I, Hemsley DR, Gray JA (1988): Differential perfor-mance of acute and chronic schizophrenics in a latent inhibi-tion task.J Nerv Ment Dis176:598–606.

Berti A (1994): Schizophrenia and substance abuse: The inter-face.Prog Neuropsychopharmacol Biol Psychiatry18:279–284.

Blaha CD, Yang CR, Floresco SB, Barr AM, Phillips AG (1997):Stimulation of the ventral subiculum of the hippocampusevokes glutamate receptor-mediated changes in dopamineefflux in the rat nucleus accumbens.Eur J Neurosci9:902–911.

Bogarts B, Lieberman JA, Ashtari M, et al (1993): Hippocam-pus-amygdala volumes and psychopathology in schizophre-nia. Biol Psychiatry33:236–246.

Bozarth MA, Wise RA (1986): Involvement of the ventraltegmental dopamine system in opioid and psychomotor stim-ulant reinforcement [Harris L, editor].NIDA Res Monogr67:190–196.

Brake WG, Sullivan RM, Flores G, Srivastava LK, Gratton A(1999): Neonatal ventral hippocampal lesions attenuate thenucleus accumbens dopamine response to stress: An electro-chemical study on the adult rat.Brain Res831:25–32.

Brudzynski SM, Gibson CJ (1997): Release of dopamine in thenucleus accumbens caused by stimulation of the subiculum infreely moving rats.Brain Res Bull42:303–308.

Buckley PF (1998): Substance abuse in schizophrenia: A review.J Clin Psychiatry59:26–30.

Bunney WE, Bunney BG (2000): Evidence for a compromiseddorsolateral prefrontal cortical parallel circuit in schizophre-nia. Brain Res Brain Res Rev31:138–146.

Burns LH, Annett L, Everett BJ, Robbins TW, Kelley AE(1996): Effects of lesions to amygdala, ventral subiculum,medial prefrontal cortex, and nucleus accumbens on thereaction to novelty: Implication for limbic-striatal interac-tions.Behav Neurosci110:60–73.

Carlezon WAJ, Devine DP, Wise RA (1995): Habit-formingactions of nomifensine in nucleus accumbens.Psychophar-macology122:194–197.

Chambers RA, Bremner JD, Moghaddam B, Southwick SM,

Neurobiology of Substance Use in Schizophrenia 79BIOL PSYCHIATRY2001;50:71–83

Charney DS, Krystal JH (1999): Glutamate and post-trau-matic stress disorder: Toward a psychobiology of dissocia-tion. Sem Clin Neuropsychiatry4:274–281.

Chambers RA, Potenza MN (2001): Schizophrenia and patho-logical gambling (letter)Am J Psychiatry158:497-498.

Chen J, Paredes W, Li J, Smith D, Lowinson J, Gardner EL(1990): Delta-9-tetrahydrocannabinol produces naloxoneblockable enhancement of presynaptic dopamine eflux innucleus accumbens of conscious, freely-moving rats as mea-sured by intracranial microdialysis.Psychopharmacology102:156–162.

Clark AJM, Feldon J, Rawlins JNP (1992): Aspiration lesions ofrat ventral hippocampus disinhibit responding in conditionedsuppression or extinction, but spare latent inhibition and thepartial reinforcement extinction effect.Neuroscience48:821–829.

Crow TJ, Deakin JFW, Longden A (1977): The nucleus accum-bens—possible site of action of antipsychotic action ofneuroleptic drugs?Physiolog Med7:213–221.

Csernansky JG, Bardgett ME (1998): Limbic-cortical neuronaldamage and the pathophysiology of schizophrenia.SchizophrBull 24:231–248.

Cuffel BJ (1992): Prevalence estimates of substance abuse inschizophrenia and their correlates.J Nerv Ment Dis180:589–592.

Cuffel BJ, Heithoff KA, Lawson W (1993): Correlates ofpatterns of substance abuse among patients with schizophre-nia. Hosp Comm Psychiatry44:247–251.

Cummings JL (1993): Frontal-subcortical circuits and humanbehavior.Arch Neurol50:873–880.

Dalack GW, Healy DJ, Meador-Woodruff JH (1998): Nicotinedependence in schizophrenia: Clinical phenomena and labo-ratory findings.Am J Psychiatry155:1490–1501.

Davis KL, Kahn RS, Ko G, Davidson M (1991): Dopamine andschizophrenia: A review and reconceptualization.Am J Psy-chiatry 148:1474–1486.

DeQuardo JR, Carpenter CF, Tandon R (1994): Patterns ofsubstance abuse in schizophrenia: Nature and significance.J Psychiatr Res28:267–275.

Deutch AY (1993): Prefrontal cortical dopamine systems and theelaboration of functional corticostriatal circuits: Implicationsfor schizophrenia and Parkinson’s disease.J Neural Transm91:197–221.

DeVries TJ, Schoffelmeer ANM, Binnekade R, VanderschurenLJMJ (1999): Dopaminergic mechanisms mediating the in-centive to seek cocaine and heroin following long-termwithdrawal of IV drug self-administration.Psychopharma-cology143:254–260.

Di Chiara G, Imperato A (1988): Drugs abused by humanspreferentially increase synaptic dopamine concentrations inthe mesolimbic system of freely moving rats.Proc Natl AcadSci U S A85:5274–5278.

Dixon L (1999): Dual diagnosis of substance abuse in schizo-phrenia: Prevalence and impact on outcomes.Schizophr Res35(suppl):S93–S100.

Dixon L, Haas G, Weidon PJ, Sweeney J, Frances AJ (1991):Drug use in schizophrenic patients: Clinical correlates andreasons for use.Am J Psychiatry148:224–230.

Dworkin SI, Goeders NE, Smith JE (1986): The reinforcing and

rate effects of intracranial dopamine administration [Harris L,editor]. NIDA Res Monogr67:242–248.

Farde L (1997): Brain imaging of schizophrenia—the dopaminehypothesis.Schizophr Res28:157–162.

Fibiger HC, Phillips AG, Brown EE (1992): The neurobiology ofcocaine-induced reinforcement.Ciba Found Symp166:96–124.

Finch DM (1996): Neurophysiology of converging synapticinputs from the rat prefrontal cortex, amygdala, midlinethalamus, and hippocampal formation onto single neurons ofthe caudat/putamen and nucleus accumbens.Hippocampus6:495–512.

Gerding LB, Labbate LA, Meason MO, Santos AB, Arana GW(1999): Alcohol dependence and hospitalization in schizo-phrenia.Schizophr Res38:71–75.

Giovino GA, Schooley MW, Zhu B, et al (1994): Surveillancefor selected tobacco-use behaviors—United States, 1990–1994. Surveillance Summaries/Morbidity and MortalityWeekly Report43:1–43.

Glassman AH, Covey LS, Dalack GW, Stetner F (1992):Cigarette smoking, major depression and schizophrenia.ClinNeuropharmacol15:560A–561A.

Glenthoj B, Mogensen J, Laursen H, Holm S, Hemmingsen R(1993): Electrical sensitization of the meso-limbic dopami-nergic system in rats: A pathogenic model of schizophrenia.Brian Res619:39–54.

Goldman-Rakic PS (1994): Working memory dysfunction inschizophrenia.J Neuropsychiatry Clin Neurosci6:348–357.

Goldstein M, Deutch AY (1992): Dopaminergic mechanisms inthe pathogenesis schizophrenia.FASEB J6:2413–2421.

Gray JA, Joseph MH, Hemsley DR, et al (1995): The role ofmesolimbic dopaminergic and retrohippocampal afferents tothe nucleus accumbens in latent inhibition: Implications forschizophrenia.Behav Brain Res71:19–31.

Gray NS, Pickering AD, Hemsley DR, Dawling S, Gray JA(1992): Abolition of latent inhibition by a single 5 mg dose ofd-amphetamine in man.Psychopharmacology107:425–430.

Groenewegen HJ, Vermeulen-Van der Zee E, te KortschotA,Witter MP (1987): Organization of the projections from thesubiculum to the ventral striatum in the rat: A study usinganterograde transport of phaseolus vulgaris leucoagglutinin.Neuroscience23:103–120.

Groenewegen HJ, Wright CI, Uylings HBM (1997): The ana-tomical relationships of the prefrontal cortex with limbicstructures and the basal ganglia.J Psychopharmacol11:99–106.

Haney M, Collins ED, Ward AS, Foltin RW, Fischman MW(1999): Effect of a selective D1 agonist (ABT-431) onsmoked cocaine self-administration in humans.Psychophar-macology143:102–110.

Haney M, Foltin RW, Fischman MW (1998): Effects of pergol-ide on intravenous cocaine self-administration in men andwomen.Psychopharmacology137:15–24.

Hoebel BG, Monaco AP, Hernandez L, Aulisi EF, Stanley BG,Lenard L (1983): Self-injection of amphetamine directly intothe brain.Psychopharmacology81:158–163.

Hoffman RE, McGlashan TH (1993): Parallel distributed pro-cessing and the emergence of schizophrenic symptoms.Schizophr Bull19:119–139.

80 R.A. Chambers et alBIOL PSYCHIATRY2001;50:71–83

Hollerman JR, Schultz W (1998): Dopamine neurons report anerror in the temporal prediction of reward during learning.Nature Neurosci1:304–309.

Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA (1986):Prevalence of smoking among psychiatric outpatients.Am JPsychiatry143:993–997.

Imperato A, Di Chiara G (1986): Preferential stimulation ofdopamine release in the nucleus accumbens of freely movingrats by ethanol.J Pharmacol Exp Ther239:219–228.

Ito R, Dalley JW, Howes SR, Robbins TW, Everitt BJ (2000):Dissociation in conditioned dopamine release in the nucleusaccumbens core and shell in response to cocaine cues andduring cocaine-seeking behavior in rats.J Neurosci20:7489–7495.

Jaffe JH, Cascella NG, Kumor KM, Sherer MA (1989): Cocaine-induced cocaine craving.Psychopharmacology97:59–64.

Jay TM, Glowinski J, Thierry AM (1995): Inhibition of hip-pocampo-prefrontal cortex excitatory responses by the meso-cortical DA system.NeuroReport6:1845–1848.

Jentsch JD, Taylor JR (1999): Impulsivity resulting from fron-tostriatal dysfunction in drug abuse: Implications for thecontrol of behavior by reward-related stimuli.Psychophar-macology146:373–390.

Joyce JN, Lexow N, Bird E, Winokur A (1988): Organization ofdopamine D1 and D2 receptors in human striatum: Receptorautoradiographic studies in Huntington’s disease and schizo-phrenia.Synapse2:546–557.

Kelley AE, Domesick VB (1982): The distribution of theprojection from the hippocampal formation to the nucleusaccumbens in the rat: An anterograde and retrograde-horse-radish peroxidase study.Neuroscience7:2321–2335.

Kelley SP, Mittleman G (1999): Effects of hippocampal damageon reward threshold and response rate during self-stimulationof the ventral tegmental area in the rat.Behav Brain Res99:133–141.

Koob GF (1992): Drugs of abuse: Anatomy, pharmacology andfunction of reward pathways.Trend Pharmacol Sci13:177–184.

Koob GF, Le Moal M (1997): Drug abuse: Hedonic homeostaticdysregulation.Science278:52–58.

Krystal JH, D’Souza DC, Madonick S, Petrakis IL (1999):Toward a rational pharmacotherapy of comorbid substanceabuse in schizophrenic patients.Schizophr Res35(suppl):S35–S49.

Lambert M, Haasen C, Mass R, Krausz M (1997): Consumptionpatterns and motivation for use of addictive drugs in schizo-phrenic patients.Psychiatr Prax24:185–189.

Laruelle M (1998): Imaging dopamine transmission in schizo-phrenia. A review and meta-analysis.Q J Nucl Med42:211–221.

Lavin A, Grace AA (1994): Modulation of dorsal thalamic cellactivity by the venral pallidum: Its role in the regulation ofthalamocortical activity by the basal ganglia.Synapse18:104–127.

Legault M, Rompre PP, Wise RA (2000): Chemical stimulationof the ventral hippocampus elevates nucleus accumbensdopamine by activating dopaminergic neurons of the ventraltegmental area.J Neurosci20:1635–1642.

Legault M, Wise RA (1999): Injections of N-Methyl-D-Aspar-

tate into the ventral hippocampus increase extracellular do-pamine in the ventral tegmental area and nucleus accumbens.Synapse31:241–249.

Lieberman JA, Kinon BJ, Loebel AD (1990): Dopaminergicmechanisms in idiopathic and drug- induced psychosis.Schizophr Bull16:97–110.

Lillrank SM, Lipska BK, Kolachana BS (1999): Attenuatedextracellular dopamine levels after stress and amphetamine inthe nucleus accumbens of rats with neonatalventral hip-pocampal damage.J Neural Transm106:183–196.

Lillrank SM, Lipska BK, Weinberger DR (1995): Neurodevel-opmental animal models of schizophrenia.Clin Neurosci3:98–104.

Ling W, Compton P, Rawson R, Wesson DR (1996): Neuropsy-chiatry of alcohol and drug abuse. In: Fogel B, Schiffer R,Rao S, editors.Neuropsychiatry.Baltimore: Williams andWilkins, 679–721.

Lipska BK, Jaskiw GE, Chrapusta S, Karoum F, Weinberger DR(1992): Ibotenic acid lesion of the ventral hippocampusdifferentially affects dopamine and its metabolites in thenucleus accumbens and prefrontal cortex in the rat.Brain Res585:1–6.

Lipska BK, Jaskiw GE, Weinberger DR (1993): Postpubertalemergence of hyperresponsiveness to stress and to amphet-amine after neonatal excitotoxic hippocampal damage: Apotential animal model of schizophrenia.Neuropsychophar-macology9:67–75.

Lopes da Silva FH, Arnolds DEAT, Neijt HC (1984): Afunctional link between the limbic cortex and ventral stria-tum: Physiology of the subiculum accumbens pathway.ExpBrain Res55:205–214.

Luchins DJ (1992): Repetitive behaviors in chronically institu-tionalized schizophrenic patients.Schizophr Res8:119–123.

Ma J, Brudzynski SM, Leung LS (1996): Involvement of thenucleus accumbens-ventral pallidal pathway in postictal be-havior induced by a hippocampal after discharge in rats.Brain Res739:26–35.

March JS (1999): Cognitive-behavioral psychotherapy. In: Sa-dock BJ, Sadock VA, editors.Kaplan and Sadock’s Compre-hensive Textbook of Psychiatry,(7th ed, Vol II). New York:Lippincott Williams & Wilkins, 2810.

Martinot JL, Paillere-Martinot ML, Loc’h C, et al (1994): CentralD2 receptors and negative symptoms of schizophrenia.Br JPsychiatry164:27–34.

Masterson E, O’Shea B (1984): Smoking and malignancy inschizophrenia.Br J Psychiatry145:429–432.

McEvoy JP, Brown S (1999): Smoking in first-episode patientswith schizophrenia.Am J Psychiatry156:1120–1121.

McGregor A, Baker G, Roberts DC (1996): Effects of 6-hy-droxydopamine lesions of the medial prefrontal cortex onintravenous cocaine self-administration under a progressiveratio schedule of reinforcement.Pharmacol Biochem Behav53:5–9.

Mittleman G, Bratt AM, Chase R (1998): Heterogeneity of thehippocampus: Effects of subfield lesions on locomotionelicited by dopaminergic agonists.Behav Brain Res92:31–45.

Mueser KT, Yarnold PR, Levinson DF, et al (1990): Prevalenceof substance abuse in schizophrenia: Demographics andclinical correlates.Schizophr Bull16:31–54.

Neurobiology of Substance Use in Schizophrenia 81BIOL PSYCHIATRY2001;50:71–83

Mugnaini E, Ortel WH (1985):An atlas of the distribution ofGABA-ergic neurons and terminals in the rat CNS as re-vealed by GAD immunohistochemistry,Vol 4. Amsterdam:Elsevier.

Mulder AB, Hodenpijl MG, Lopez de Silva FH (1998): Electro-physiology of the hippocampal and amygdaloid projections tothe nucleus accumbens of the rat: Convergence, segregation,and interactions of inputs.J Neurosci18:5095–5102.

Naber PA, Witter MP (1998): Subicular efferents are organizedmostly as parallel projections: A double-labeling, retrograde-tracing study in the rat.J Comp Neurol393:284–297.

Nordstrom AL, Farde L, Eriksson L, Halldin C (1995): Noelevated DZ dopamine receptors in neuroleptic-naive schizo-phrenic patients revealed by positron emission tomographyand [nc] N-methylspiperone.Psychiatry Res61:67–83.

O’Donnell P, Grace AA (1994): Tonic D2-mediated attenuationof cortical excitation in nucleus accumbens neurons recordedin vitro. Brain Res634:105–112.

O’Donnell P, Grace AA (1996): Dopaminergic reduction ofexcitability in nucleus accumbens neurons recorded in vitro.Neuropsychopharmacology15:87–97.

O’Donnell P, Greene J, Pabello N, Lewis BL, Grace AA (1999):Modulation of cell firing in the nucleus accumbens.Ann N YAcad Sci877:157–175.

O’Donnell PO, Grace AA (1995): Synaptic interactions amongexcitatory afferents to the nucleus accumbens neurons: Hip-pocampal gating of prefrontal cortical input.J Neurosci15:3622–3639.

O’Farrell TJ, Conners GJ, Upper D (1983): Addictive behaviorsamong hospitalized psychiatric patients.Addict Behav8:329–333.

Pennartz CMA, Groenewegen HJ, Lopez da Silva FH (1994):The nucleus accumbens as a complex of functionally distinctneuronal ensembles: An integration of behavioral, electro-physiological and anatomical data.Prog Neurobiol42:719–761.

Piazza PV, Rouge-Pont F, Deminiere JM, Kharoubi M, Moal M,Simon H (1991): Dopaminergic activity is reduced in theprefrontal cortex and increased in the nucleus accumbens ofrats predisposed to develop amphetamine self-administration.Brain Res567:169–174.

Pohl R, Yergani VK, Balon R, Lycaki H, McBride R (1992):Smoking in patients with panic disorder.Psychiatry Res43:253–262.

Reigier DA, Farmer ME, Rae DS, et al (1990): Comorbidity ofmental disorders with alcohol and other drugs of abuse.JAMA264:2511–2518.

Reinstein DK, Hannigan JH, Isaacson RL (1982): Time course ofcertain behavioral changes after hippocampal damage andtheir alteration by dopaminergic intervention into nucleusaccumbens.Pharmacol Biochem Behav17:193–202.

Richardson NR, Smith AM, Roberts DC (1994): A singleinjection of either flupenthixol decanoate or haloperidoldecanoate produces long-term changes in cocaine self-admin-istration in rats.Drug Alcohol Depend36:23–25.

Roberts DC, Vickers G (1987): The effects of haloperidol oncocaine self-administration is augmented with repeated ad-ministrations.Psychopharmacology93:526–528.

Sandyk R, Awerbuch GI (1993): Late onset schizophrenia:

Relationship to awareness of abnormal involuntary move-ments and tobacco addiction.Int J Neurosci71:9–19.

Saul’skaya NB, Gorbachevskaya AI (1998): Conditioned reflexrelease of dopamine in the nucleus accumbens after disrup-tion of the hippocampal formation in rats.Neurosci BehavPhysiol28:380–385.

Schaub CL, Schnelzeis MC, Mittleman G (1997): The effects oflimbic lesions on locomotion and stereotypy elicited bydopamine agonists in the rat.Behav Brain Res84:129–143.

Scheibel AB, Conrad AS (1993): Hippocampal dysgenesis andschizophrenic man: Is there a relationship?Schizophr Bull19:21–33.

Schenk S, Horger BA, Peltier R, Shelton K (1991): Supersensi-tivity to the reinforcing effects of cocaine following 6-hy-droxydopamine lesions to the medial prefrontal cortex in rats.Brain Res543:227–235.

Schmajuk NA, Christiansen B, Cox L (2000): Haloperidolreinstates latent inhibition impaired by hippocampal lesions:Data and theory.Behav Neurosci114:659–670.

Schmelzeis MC, Mittleman G (1996): The hippocampus andreward: Effects of hippocampal lesions on progressive-ratioresponding.Behav Neurosci110:1049–1066.

Schottenfeld R, Carol K, Rounsaville B (1993): Comorbidpsychiatric disorders and cocaine abuse.NIDA Res Monogr135:31–47.

Seeman P, Nitznik HB (1990): Dopamine receptors and trans-porters in Parkinson’s disease and schizophrenia.FASEB J4:2737–2744.

Seeman P, Niznik HB, Guan HC, Booth G, Ulpian C (1989):Link between D1 and D2 dopamine receptors is reduced inschizophrenia and Huntington diseased brain.Proc Natl AcadSci U S A86:10156–10160.

Seibyl JP, Satel SL, Anthony D, Southwick SM, Krystal JH,Charney DS (1993): Effects of cocaine on hospital course inschizophrenia.J Nerv Ment Dis181:31–37.

Selemon LD, Goldman- Rakic PS (1999): The reduced neuropilhypothesis: A circuit based model of schizophrenia.BiolPsychiatry45:17–25.

Self DW (1998): Neural substrates of drug craving and relapse indrug addiction.Ann Med30:379–389.

Self DW, Bernhart WJ, Lehman DA, Nestler EJ (1996): Oppositemodulation of cocaine-seeking behavior by D1- and D2-likedopamine receptor agonists.Science271:1586–1589.

Self DW, Nestler EJ (1998): Relapse to drug-seeking: Neural andmolecular mechanisms.Drug Alcohol Depend51:49–60.

Self DW, Terwilliger RZ, Nestler EJ, Stein L (1994): Inactiva-tion of Gi and Go proteins in nucleus accumbens reduces bothcocaine and heroin reinforcement.J Neurosci14:6239–6247.

Selzer JA, Lieberman JA (1993): Schizophrenia and substanceabuse.Psychiatr Clin N A16:401–412.

Sesack SR, Pickel VM (1990): In the rat medial nucleusaccumbens, hippocampal and catecholaminergic terminalconverge on spiny neurons and are in apposition to eachother.Brain Res527:266–279.

Shaham Y, Stewart J (1996): Effects of opioid and dopaminereceptor antagonists on relapse induced by stress and re-exposure to heroin in rats.Psychopharmacology125:385–391.

82 R.A. Chambers et alBIOL PSYCHIATRY2001;50:71–83

Shippenberg TS, Hertz A (1987): Place preference reveals theinvolvement of D-1dopamine receptors in the motivationalproperties of mu and kappa-opioid agonists.Brain Res436:169–172.

Sinha R, Catapano D, O’Malley S (1999): Stress induced cravingand stress response in cocaine dependent individuals.Psycho-pharmacology142:343–351.

Skopec M, Rosenberg SD, Tucker GJ (1976): Sexual behavior inschizophrenia.Med Aspects Hum Sex10:32–47.

Stewart J (2000): Pathways to relapse: The neurobiology of drug-and stress-induced relapse to drug taking.J PsychiatryNeurosci25:125–136.

Strakowski SM, Tohen M, Flaum M, Amador X (1994): Sub-stance abuse in psychotic disorders: Associations with affec-tive syndromes.Schizophr Res14:73–81.

Sumiyoshi T, Stockmeier CA, Overholser JC, Thompson PA,Meltzer HY (1995): Dopamine D4 receptors and effects ofguanine nucleotides on (3H) raclopride binding in postmor-tem caudate nucleus of subjects with schizophrenia or majordepression.Brain Res681:109–116.

Sunahara RK, Seeman P, Van Tol HH, Niznik HB (1993):Dopamine receptors and antipsychotic drug response.Br JPsychiatry22:31–38.

Tanda G, Pontieri FE, Di Chiara G (1997): Cannabinoid andheroin activation of mesolimbic dopamine transmission by acommon mu1 opioid receptor mechanism.Science 276:2048–2050.

Todd C, Grace AA (1999): Modulation of ventral tegmental areadopamine cell activity by the ventral subiculum and entorhi-nal cortex.Ann N Y Acad Sci877:688–690.

Totterdell S, Smith AD (1989): Convergence of hippocampal anddopaminergic input onto identified neurons in the nucleusaccumbens of the rat.J Chem Neuroanat2:285–298.

Van Ammers EC, Sellman JD, Mulder RT (1997): Temperamentand substance abuse in schizophrenia: Is there a relationship?J Nerv Ment Dis185:283–288.

Volkow ND, Fowler JS (2000): Addiction, a disease of compul-sion and drive: Involvement of the orbitofrontal cortex.CerebCortex10:318–325.

Walker EF, Diforio D (1997): Schizophrenia: A neural diathesis-stress model.Psychol Rev104:667–685.

Weinberger DR, Aloa MS, Goldberg TE, Berman KF (1994):The frontal lobes and schizophrenia.J Neuropsychiatry6:419–427.

Weinberger DR, Lipska BK (1995): Cortical maldevelopment,anti-psychotic drugs, and schizophrenia: A search for com-mon ground.Schizophr Res16:87–110.

Weiner I (1990): Neural substrates of latent inhibition: Theswitching model.Psychol Bull108:442–461.

Weissenborn R, Deroche V, Koob G, Weiss F (1996): Effects ofdopamine agonists and antagonists on cocaine-induced oper-ant responding for a cocaine-associated stimulus.Psycho-pharmacology126:311–322.

Whishaw IQ, Mittleman G (1991): Hippocampal modulation ofnucleus accumbens: Behavioral evidence from amphetamine-induced activity profiles.Behav Neural Biol55:289–306.

White FJ, Kalivas PW (1998): Neuroadaptations involved inamphetamine and cocaine addiction.Drug Alcohol Depend51:141–153.

Wilkinson LS, Mittleman G, Torres E, Humbly T, Hall FS,Robbins TW (1993): Enhancement of amphetamine-inducedlocomotor activity and dopamine release in nucleus accum-bens following excitotoxic lesions of the hippocampus.BehavBrain Res55:143–150.

Wise RA (1990): The role of reward pathways in the develop-ment of drug dependence. In: Balfour D, editor.PsychotropicDrugs of Abuse.Oxford, UK: Pergamon Press, 23–57.

Yang CQ, Kitamura N, Nishino N, Shirakawa O, Nakai H(1998): Isotype-specific G protein abnormalities in the leftsuperior temporal cortex and limbic structures of patientswith chronic schizophrenia.Biol Psychiatry43:12–19.

Yang C, Mogenson GJ (1984): Electrophysiological responses ofneurons in the nucleus accumbens to hippocampal stimulationand the attenuation of the excitatory responses by the me-solimbic dopaminergic system.Brain Res324:69–84.

Yang CR, Mogensen GJ (1985): An electrophysiological studyof the neural projections from the hippocampus to the ventralpallidum and the subpallidal areas by way of the nucleusaccumbens.Neuroscience15:1015–1024.

Zisook S, Heaton R, Moranville J, Kuck J, Jernigan T, Braff D(1992): Past substance abuse and clinical course of schizo-phrenia.Am J Psychiatry149:552–553.

Neurobiology of Substance Use in Schizophrenia 83BIOL PSYCHIATRY2001;50:71–83