Nicotine and schizophrenia

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1492 Am J Psychiatry 155:11, November 1998

NICOTINE DEPENDENCE IN SCHIZOPHRENIA

In some of these studies (35, 25), a small propor-tion of the nonsmokers reported that they had previ-ously smoked. Generally, sufficient details are not re-ported to ascertain whether there are differences insmoking history or level of addiction between currentand former smokers with schizophrenia. The retro-spective reports of our small group of former smokers

suggested that they were less addicted smokers whenthey were smoking (27). There is also some suggestionthat former smokers have higher levels of functioningand fewer negative symptoms than current smokerswith schizophrenia (28).

Clinical Correlates of Schizophrenia AssociatedWith Smoking Status

In a number of cross-sectional studies (3, 4, 24, 29),current smoking in inpatient and outpatient settingshas frequently been associated with younger age, ear-lier age at onset of schizophrenia, more hospitaliza-tions, and higher doses of neuroleptic medication. If

smoking were a form of self-medication for schizo-phrenia, one might expect to find some correlation ofpsychiatric symptoms with smoking status. Goff et al.(3) found that smokers had a higher total score on theBrief Psychiatric Rating Scale (BPRS) (30) and higherBPRS subscale scores for both positive and negativesymptoms. Ziedonis et al. (4) also found more positivesymptoms among smokers than among nonsmokers.In addition, heavy smokers (defined as those smokingmore than 25 cigarettes per day) had the highest num-ber of positive symptoms and the lowest number ofnegative symptoms in comparison with light smokersand nonsmokers with schizophrenia. Hall et al. (28)

reported that former smokers with schizophrenia hadfewer negative symptoms (BPRS subscale) than smok-ers. The relationships between psychiatric symptomsand smoking in cross-sectional associations are diffi-cult to interpret. It may be that smoking is a marker ofmore severe psychiatric illness. Alternatively, it may bethat smoking is associated with some increase in psy-chiatric symptoms; there are few data to support thisassertion, however.

In their study, Glynn and Sussman (25) surveyedsmokers with schizophrenia to assess their reasons forsmoking. For the most part, subjects reported smokingfor many of the same reasons that nonpsychiatricallyill smokers do, including relaxation, habit, and

settling nerves (p. 1027). They also reported similarwithdrawal symptoms. About 28% of the subjects saidthat they smoked in part because of psychiatric symp-toms. Several of these patients reported increased psy-chiatric symptoms during withdrawal from tobacco.We have reported our own experience of three cases ofexacerbation of psychiatric symptoms in smokers withschizophrenia who cut back or briefly abstained fromsmoking (31). Hamera et al. (32) also examined the re-lationship between self-reported psychiatric symptomsand nicotine use. They found that self-report of symp-

toms signaling an exacerbation of illness was associ-ated with decreased nicotine use. Conclusions fromthese reports are limited, however, because the tempo-ral relationship between symptom changes and smok-ing behavior was not prospectively studied, nor wasthere an objective measure of smoking (e.g., nicotinelevels) beyond subjects self-reports about the number

of cigarettes smoked.One report addressed the specificity of the relation-

ship between smoking and schizophrenia amongchronically hospitalized psychiatric patients: de Leonet al. (23) found that schizophrenia was associatedwith an increased likelihood of being both a smokerand a heavy smoker (smoking more than 1.5 packs perday). However, smoking was not related to duration ofhospitalization or to neuroleptic dose among patientswith schizophrenia.

Correlations between smoking and movement disor-ders have also received special attention. Several cross-sectional reports have suggested that cigarette smoking

is associated with a decrease in the likelihood of idio-pathic Parkinsons disease. It has been speculated thatthis may be due to the effect of nicotine on striatal do-pamine systems affected in this condition (33). Simi-larly, there is evidence to suggest that smoking is asso-ciated with a reduced incidence of neuroleptic-inducedparkinsonism. Several studies (3, 29, 34) found thatmeasures of neuroleptic-induced parkinsonism werelower among smokers than among nonsmokers withschizophrenia who were treated with neuroleptics.This finding is not uniformly held, however (35).

Several studies suggest that tardive dyskinesia andsmoking may also be associated. Yassa et al. (36) re-

ported that tardive dyskinesia was more prevalentamong smokers than among nonsmokers with schizo-phrenia who were treated with neuroleptics, whileGoff et al. (3) reported a trend for a lower AbnormalInvoluntary Movement Scale score (37) among smok-ers in comparison with nonsmokers. Others (35) foundno difference. As noted above, Nilsson et al. (18) re-ported results from a large, older male populationsample and found that dyskinesias were strongly andindependently associated with exposure to neurolep-tics and daily cigarette smoking. Indeed, the risk ofdyskinesias increased with the number of cigarettessmoked per day. This raises another important public

health issue, particularly for smokers who are exposedto neuroleptic medications, a group in which smokerswith schizophrenia are likely to be overrepresented.Beyond long-term smoking exposure and dyskinesia,there is also some suggestion that acute exposure tonicotine may increase dyskinetic movements (38).Hence, the temporal relationship between the last cig-arette smoked and evaluation for tardive dyskinesianeeds to be clearly defined in order to interpret shorter-term changes in abnormal involuntary movementswith smoking.


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Am J Psychiatry 155:11, November 1998 1493

DALACK, HEALY, AND MEADOR-WOODRUFF

Experimental Studies of Nicotine, Smoking,and Schizophrenia: Clinical Measures

Observations linking smoking and schizophreniahave been generally cross-sectional and mostly retro-spective. Clinical experimental paradigms have the po-tential to define these relationships further and to in-

form our understanding of the connections betweenclinical phenomena and basic neurophysiological func-tions central to schizophrenia and smoking. Work inthis area includes studies in which nicotine exposurewas the independent variable, and physiological andcognitive measures in schizophrenia were the depen-dent measures (3942).

Adler et al. (39, 40) examined the effects of nicotineon sensory gating, assessed by measuring auditoryevoked responses, in subjects with schizophrenia. Di-minished gating of the P50 auditory evoked responseto repeated stimuli is typically present in this popula-tion. The trait is shared by one-half of first-degree rel-atives unaffected with schizophrenia (43). Adler et al.

(39) showed that nicotine delivered by nicotine gumtransiently reversed the sensory gating deficit in non-smoking relatives of individuals with schizophrenia. Inaddition, nicotine delivered by ad lib smoking tran-siently reversed the P50 auditory evoked response gat-ing deficit in smokers with schizophrenia. These resultshave implications for the modulation by nicotine ofabnormalities in neurophysiological function found inschizophrenia. The fact that these abnormalities occurand can be briefly reversed by nicotine administrationin nonaffected relatives of probands with schizophre-nia suggests a genetic basis for the deficit, possibly in-volving CNS nicotine receptor function. In an elegantextension of these observations (44), the same group of

investigators has reported genetic linkage for this gat-ing deficit, with the gene for one type of nicotinic re-ceptor expressed in the human hippocampus. Thisfinding provides genetic evidence linking nicotinicfunction with a potential pathophysiological trait asso-ciated with schizophrenia (also see below).

Olincy et al. (42) showed that cigarette smoking im-proves some of the smooth pursuit eye movement ab-normalities found in schizophrenic subjects comparedwith nonschizophrenic subjects. This effect may be re-lated to the higher nicotine doses self-administered byschizophrenic patients and does not appear to be a re-versal of nicotine-withdrawal effects by smoking.

Levin et al. (41) followed up observations about theeffects of nicotinic systems on cognitive function (45)to study the interactions of nicotine and haloperidoltreatment on cognitive performance among subjectswith schizophrenia. They found that nicotine (admin-istered through a transdermal skin patch) reversedsome of the haloperidol dose-related impairments in avariety of cognitive tests that assay memory perfor-mance and reaction time to a complex spatial task. Inaddition, nicotine administration improved attentive-ness during a continuous performance task, indepen-dent of haloperidol dosage. That study suggests that

smoking may have important effects in improving thecognitive side effects of treatment with typical antipsy-chotic agents.

Experimental Studies of Nicotine, Smoking,and Schizophrenia: Antipsychotic Medications

Smoking results in increased metabolism of neuro-leptics (46, 47). This pharmacokinetic effect has beenshown to result in 1) an increased average dose of anti-psychotic medication to achieve similar blood levels insmokers compared with nonsmokers (46) or 2) similaraverage doses of antipsychotics with lower blood levelsin smokers compared with nonsmokers (46, 47).

At the same time, the choice of pharmacologicaltreatment is likely to have some influence on smokingbehavior. George et al. (48) reported that outpatientswith schizophrenia retrospectively reported a decreasein smoking (daily cigarette consumption) after treat-ment with the atypical agent clozapine compared withtheir smoking when treated with typical antipsychot-

ics. This suggests that smoking behavior might bedriven by the differential efficacy of clozapine and typ-ical antipsychotics in treating positive and negativesymptoms of schizophrenia or by their different sideeffect profiles. Dawe et al. (49) had already shown thatadministration of 5 mg of haloperidol to normal smok-ers resulted in an increase in nicotine intake comparedwith baseline smoking. These authors inferred that do-paminergic blockade (specifically, substantial D2blockade) resulted in a decrease in dopaminergicallymediated reward and a compensatory increase in nico-tine intake to maintain levels of subjective reward.

McEvoy et al. (50, 51) studied the effect on smokingbehavior of pharmacological treatment of schizo-

phrenic patients with haloperidol and clozapine. Theyfound that treatment with haloperidol resulted in anincrease in smoking and nicotine blood levels com-pared with a baseline medication-free condition (50).In a similar group of smokers with schizophrenia, thenumber of cigarettes smoked and the amount of car-bon monoxide in expired air decreased after 12 weeksof clozapine treatment compared with baseline mea-sures during haloperidol treatment (51). It is interest-ing to note that clozapine treatment has also beenshown to improve gating of the P50 auditory evokedresponse (52). This suggests that the modulation ofsmoking by clozapine treatment may be mediated inpart by similar effects on sensory gating. It remains to

be determined whether these differences are also re-lated to changes in psychiatric symptoms (i.e., differen-tial treatment efficacy), changes in side effects of med-ications, or both.

Neurochemical Correlates Relating Smokingand Schizophrenia

Current models of schizophrenia are predicated onregional differences in dopaminergic activity (53) andthe interactions of glutamatergic, dopaminergic (54,55), and serotonergic neurotransmitter systems (56).


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There is considerable evidence for nicotinergic modu-lation of midbrain dopamine neurons and cortical glu-tamatergic cells. The diversity of receptor subtypes forthose two neurotransmitters (57, 58), the interactionsbetween glutamatergic and dopaminergic systems, andthe potential for regional specificity of dopaminergicand glutamatergic activity all make for a complexmodel of dopaminergic and glutamatergic interactionsin brain function, with many possible sites of dysfunc-tion in schizophrenia. The influence of nicotinergic ac-tivity in modulating these systems adds an additionallayer to this complexity. However, a clearer under-standing of the heterogeneity of nicotinic receptor ex-

pression and regional specificity of nicotinergic activityas a modulator of other neurotransmitter systems isnecessary before one can advance the understanding ofthe way in which cigarette smoking and schizophreniamay be linked.

THE NICOTINIC RECEPTOR: STRUCTURE,

PHARMACOLOGY, AND ROLE IN MODULATION

OF NEUROTRANSMITTER SYSTEMS IMPLICATED

IN SCHIZOPHRENIA

This section begins with a review of the distributionand pharmacology of the nicotinic receptors in the brain.

Data describing the interactions of nicotinergic systemswith dopaminergic and glutamatergic activity, respec-tively, are then summarized. Finally, complex interac-tions simultaneously involving nicotinergic, dopaminer-gic, and glutamatergic neurotransmission are described.

Distribution and Pharmacology of Nicotinic Receptors

The neuronal nicotinic receptor is a ligand-gated ionchannel receptor similar to many glutamate and -ami-nobutyric acid (GABA) receptors. These receptors arecomposed of five subunits that are assembled to form

an ion channel, which opens when the associatedligand binds to the proper site(s). The properties of areceptor can be modified depending on what subunitsare included in the final receptor, a feature common tomost families of ligand-gated ion channels. There aremultiple nicotinic receptor subunits, each encoded by aseparate gene. The two families of neuronal nicotinicreceptor subunits are named and because of theirhomology with the muscle nicotinic receptor subunits1 and 1. There are multiple subtypes of both the and the subunits (29, 24). Usually, nicotinicreceptors contain two subunits and three subunits,although there are nicotinic receptors that contain five

identical subunits (59).Two acetylcholine molecules are required to activate

neuronal nicotinergic receptors that open the ion chan-nel, allowing calcium entry into the cell (60). Thesebinding sites are associated with the subunits. Thisactivation appears to be short-lived, however, and atime-dependent decrease in activation is observed (59).This has been interpreted as suggesting that after briefstimulation, the receptor becomes insensitive to furtheragonist exposure, a phenomenon that is termed desen-sitization (59). Desensitization limits the activity ofnicotinic receptors in response to ligand binding andappears to underlie some of the difficulties in under-standing the possible role of nicotinic receptors in the

pathophysiology of schizophrenia. In addition, thevaried pharmacodynamics of the different subunitcombinations create further difficulty in teasing outthe function of nicotinic receptors (61).

Binding studies demonstrate at least three types ofnicotinic receptors that have distinct subunit composi-tions (figure 1), pharmacological and electrophysiolog-ical properties, and neuroanatomical distributions (ta-ble 1). The most abundant type of receptor avidlybinds [3H]nicotine. These binding sites constitute 90%of all nicotinergic sites in the brain and contain 4 and

FIGURE 1. Subunit Combinations of Three Nicotinic Receptor Subtypesa

a Each subtype is believed to be composed of obligatory subunits (high-affinity [3H]nicotinic=42; neuronal bungarotoxin=32; -bunga-rotoxin=7). However, there is variability in the other subunits that may comprise nicotinic receptors, and these potential subunits are in-dicated in parentheses.


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2 subunits (59). Sites that have high affinity for thesnake neurotoxin, -bungarotoxin, are composed ex-clusively of 7 subunits (i.e., five 7 subunits consti-tute the receptor) (59). The binding sites associatedwith the neurotoxin neuronal bungarotoxin are, atleast in part, composed of 3 subunits (62). It remainsto be determined what other and subunits are con-tained in these receptors.

All of these nicotinic receptor subtypes are located inregions of the human brain that have been implicatedin schizophrenia. [3H]Nicotine binding sites are abun-dant in the striatum and substantia nigra, have moder-

ate levels of expression in the neocortex, and havelower levels of expression in the hippocampus (6366).-Bungarotoxin binding sites have also been localizedin the midbrain, neocortex, and hippocampus, withlower levels in the striatum (63, 65). Neuronal bunga-rotoxin sites are abundant in the hippocampus andneocortex but are present in much lower levels in themidbrain (62, 63). Within the neocortex itself, the pat-tern of distribution of two of these binding sites is lam-ina-specific: [3H]nicotine sites are preferentially dis-tributed in supragranular cortical laminae (II and III)(64), and neuronal bungarotoxin sites are preferen-tially localized to infragranular laminae (V and VI)(62). -Bungarotoxin sites are less abundant in the

cortex than the other two nicotinic binding sites anddo not appear to display differential laminar distribu-tion (63). The relative enrichment of the [3H]nicotinebinding site in supragranular layers and the neuronalbungarotoxin binding site in infragranular layers is in-triguing, given that the supragranular pyramidal neu-rons tend to project to other cortical regions, while in-fragranular pyramidal neurons typically project tosubcortical structures. On the basis of these anatomi-cal differences, there may be specific functional rolesfor [3H]nicotine sites in corticocortical information pro-cessing and neuronal bungarotoxin sites in cortical-sub-cortical communication, both of which may be disruptedin schizophrenia. It is conceivable that both the hypo-frontality and the cortical-subcortical dysregulation thathave been hypothesized in schizophrenia (53) may bemitigated, in part, by self-administration of nicotine thatactivates or desensitizes these particular receptors.

The following sections review studies examining thenicotinic modulation of dopaminergic and glutamater-gic neurotransmission, with particular emphasis onstudies focusing on limbic regions. Controversy sur-rounds the issue of which nicotine administration sched-ules in animal studies most accurately reflect the dosingschedule experienced by smokers. Therefore, we have

summarized studies that have used one of the followingdosing schedules: acute dosing (one-time injection),chronic intermittent treatment (daily injections for manydays), chronic continuous infusion with minipumps, andchronic infusion followed by acute challenge.

Nicotine-Dopamine Interactions

Differences between nigrostriatal and mesocortico-limbic dopamine systems. The dopaminergic neuronsin the ventral tegmental area and the substantia nigra,pars compacta, provide the majority of dopaminergic

innervation to the forebrain. The ventral tegmentalarea projects to the nucleus accumbens, the cortex,and many limbic regions (mesocorticolimbic system),while the substantia nigra, pars compacta, projects pri-marily to the dorsal striatum (nigrostriatal system) (67).These two parallel systems subserve limbic and motorfunctions, respectively (figure 2). Nicotine treatment ap-pears to differentially affect dopamine release, dopaminemetabolism, and the electrophysiological properties ofdopamine neurons in these two functional systems.

Ventral tegmental area neurons and substantia nigra,pars compacta, neurons display basal firing rates withbrief periods of very rapid firing (burst firing). Acutenicotine treatment causes an increase in both the firing

rate and burst firing of substantia nigra, pars compacta,neurons but only an increase in burst firing of ventral teg-mental area neurons (68, 69). Acute treatment withmecamylamine, a nicotine receptor antagonist, causes adecrease in basal firing rate in ventral tegmental areaneurons but not in substantia nigra, pars compacta, neu-rons (68). It is interesting that chronic continuous nico-tine administration has the same electrophysiological ef-fect as the antagonist mecamylamine; this is thought tobe due to desensitization of the nicotinic receptor (70).

Taken together, these studies suggest the presence ofmaximally driven tonic cholinergic input to the ventraltegmental area, mediated by nicotinic receptors, suchthat the basal firing rate of ventral tegmental area neu-rons is not increased by exogenous nicotine. This is incontrast to the substantia nigra, pars compacta, wherethere does not appear to be tonic cholinergic input. Con-sistent with this interpretation is the relative insensitivityto up-regulation of nicotinic receptors on ventral teg-mental area neurons in comparison with substantia ni-gra, pars compacta, neurons (71). In addition, the differ-ences in firing rates and burst firing result in differentialdopamine release from cells originating in the ventraltegmental area and substantia nigra, pars compacta. Spe-cifically, nicotine treatment much more efficiently causes

TABLE 1. Characteristics of Nicotinic Receptor Subtypes

Characteristic High-Affinity [3H]Nicotine Neuronal Bungarotoxin Bungarotoxin

Abundance in brain Most Least IntermediateDistribution Striatum=midbrain>cortex>

hippocampusCortex=hippocampus>striatum>

midbrainMidbrain=cortex=hippocampus>

striatumCalcium conductance Intermediate Smallest HighestInactivation due to desensitization Slow Slowest RapidCortical laminar distribution Supragranular Infragranular Equal distribution in all layers


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dopamine release in the nucleus accumbens than in thedorsal striatum (72, 73) (figure 3).

Further, dopamine metabolism also appears to bedifferentially regulated in limbic and motor systems bynicotine treatment. Animal studies indicate that acutenicotine treatment increases dopamine synthesis andcatabolism in the nucleus accumbens but not in thedorsal striatum (74, 75). On the other hand, chroniccontinuous nicotine treatment decreases dopamine ca-tabolism in the dorsal striatum but not in the nucleusaccumbens (76). A precedent for altered dopamine me-tabolism exists in humans as well. The 40% decreasein monoamine oxidase B activity in the brains of smok-ers compared with nonsmokers may provide an addi-tional mechanism for enhancing the effects of nicotine-related dopamine release (77).

The net effect of nicotine on dopaminergic neuronfiring and dopamine turnover is to enhance dopaminelevels in the nucleus accumbens relative to the dorsalstriatum. These activities are believed to be an impor-tant part of the neurobiological substrate of nicotinesaddictive properties (78). As such, these effects maynot have any specific relevance to schizophrenia. On

the other hand, it is possible that the anhedonic, amo-tivational negative symptoms of schizophrenia are amanifestation of an abnormal reward-reinforcementsystem (79). In that case, the observation that smokerswith schizophrenia have more negative symptoms thannonsmokers with the illness suggests that smoking maybe an attempt to self-medicate a disturbance in the re-ward circuitry in the ventral striatum. This is a specula-tive interpretation, and it is confounded by the ubiqui-tous use of antipsychotic medications, since these alsoaffect dopaminergic systems. An alternative view is thatsmoking may represent an effort to overcome medica-tion-related accumbens dopaminergic blockade (49).

In addition to differential cholinergic input, thesedifferences in dopamine metabolism and release in thenigrostriatal and mesocorticolimbic systems may bemediated by differences in the subunit composition ofnicotinic receptors in these different brain regions.Functional measures of nicotine response provide indi-rect evidence for heterogeneity in nicotinic receptorpharmacology, since different subunit combinationsprobably confer unique pharmacological properties. Inparticular, a potential substrate for pharmacological

FIGURE 2. Schematic Representation of Cortico-Striato-Pallido-Thalamic Circuitrya

a These circuits subserve limbic and motor activities. In particular, they appear to modulate striatal input and outflow, which are critical forthe execution of motor behavior (caudate, putamen, and nucleus accumbens, core) and limbic behavior (nucleus accumbens, shell). Theglutamatergic input from the cortex and the dopaminergic input from the midbrain converge in the striatum, and both dopamine and

glutamate activities are modulated by cholinergic input mediated by nicotinic receptors (see detail).


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differences may be the difference in neuroanatomicaldistribution of the 3 subunit. ABT-418 and isoare-colone are nicotinic receptor agonists with a muchhigher affinity for receptors that contain the 4 sub-unit than those containing the 3 subunit (80, 81).Treatment with ABT-418 is three times less potent atactivating ventral tegmental area neurons than nico-

tine (80), while isoarecolone is much less potent thannicotine at stimulating dopamine release in the nucleusaccumbens (81). On the basis of these findings, it isconceivable that there are more 3-subunit-containingreceptors in the accumbens than in the dorsal striatum,which mediates this pattern of differential dopaminerelease in those regions by nicotine. A potential sub-population of receptors fitting this profile has beenidentified in a study by Schulz et al. (82) of the effectsof aging on dopamine release. These investigatorsfound a 2.5-fold difference in dopamine release in stri-atal slices from young rats in comparison with thosefrom old rats. They suggested that diminished releasein the old rats was due to an 80% reduction in a sub-

population of 3-subunit-containing receptors, deter-mined by neuronal bungarotoxin binding. The factthat there is an appreciable effect on dopamine releasewhen receptor composition changes provides supportfor the hypothesis that subunit differences may medi-ate regionally specific patterns of dopamine release.

The regional specificity of nicotinic receptor distri-bution is also supported by several studies which sug-gest that individual brain regions express different nic-otinic receptor subunit mRNAs. The most commonnicotine receptor subunits are 4 and 2, and high-af-finity nicotine binding sites are associated with theconcomitant presence of both (59). However, the ratioof 4 mRNA to 2 mRNA varies in different brain re-

gions, suggesting that there are other subunits co-as-sembled in the final receptors in these regions (83).There is evidence to support the inclusion of other subunits and/or subunits in the final receptor. Nico-tinic receptors composed of 44234 have beenrecently isolated from rat striatum and shown to havehigh affinity for nicotine (84). In addition, midbraindopaminergic nuclei have higher levels of 5, 6, and3 subunits than 4 or 2 subunits (85), so there re-mains the potential for unique combinations of nico-tinic receptor subunits and considerable complexity ofnicotinic receptors. These subunit combinations mayconfer unique pharmacological properties.

The total nicotinic activation in a region appears tobe determined by the relative proportions of differentpopulations of nicotinic receptors with varying subunitcomposition. This diversity may explain some of thedifferences of nicotine response in limbic versus motordopamine systems, but the confirmation of this expla-nation awaits further study of the specific subunitcomposition of nicotinic receptors in these regions.Given the evidence that at least one subtype of nico-tinic receptor is differentially expressed in schizophre-nia (44), it is tempting to speculate that different com-binations of nicotinic receptor subunits may exist

between schizophrenic and normal subjects and possi-bly between schizophrenic smokers and schizophrenicnonsmokers. Investigation of such potential differ-ences would have implications for our understandingof both schizophrenia and nicotine addiction.

Differences between cortical and subcortical dopa-mine activity. In addition to the dissociation of nico-tinic modulation of mesocorticolimbic and nigrostria-tal dopaminergic systems, there appear to be signifi-

FIGURE 3. Schematic Representation of the Interaction of Nic-otine, Glutamate, and Dopamine in Striatal Regionsa

a Glutamatergic neurons from the cerebral cortex project onto do-paminergic neurons from the substantia nigra, pars compacta,

and ventral tegmental area in the caudate-putamen and nucleusaccumbens, shell, respectively. The caudate-putamen subservesmotor functions, and evidence suggests that nicotinic receptors ofthe high-affinity subtype (designated 42) modulate the releaseof dopamine (DA) either directly, through a presynaptic mecha-nism on dopaminergic projections from the substantia nigra, or in-directly, through cortical glutamatergic projections. Nicotinic re-ceptors of the 42 subtype are believed to presynapticallyincrease glutamate (GLU) release from corticostriatal terminals,which in turn activates a glutamate receptor, leading to dopaminerelease in the caudate-putamen. Similar mechanisms appear tooccur in the nucleus accumbens, shell, except that there appearsto be a higher percentage of nicotinic receptors of the neuronalbungarotoxin subtype (designated 32) located in the nucleusaccumbens, shell. This relative enrichment of 32 nicotinic re-ceptors in the nucleus accumbens, shell, is postulated to underliethe greater dopamine release in that area compared with the cau-

date-putamen (indicated by more dopamine in synapses).


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cant differences in nicotinic regulation of cortical andsubcortical dopamine activity. Acute nicotine treat-ment increases dopamine levels in the dorsal striatumand prefrontal cortex (86), while chronic nicotinetreatment does not affect dopamine levels in either re-gion (76). However, acute challenge with nicotine afterchronic treatment causes an increase in dopamine lev-

els in the prefrontal cortex but not in the nucleus ac-cumbens (86), suggesting that chronic nicotine treat-ment produces an alteration in cortical nicotinicreceptor activity that results in altered sensitivity tonicotine. Consistent with this idea, nicotine-mediateddopamine metabolism differs in the cortex and the stri-atum. Acute nicotine treatment regulates dopaminesynthesis and catabolism in the nucleus accumbens butnot in the prefrontal cortex (87). Conversely, bothchronic intermittent and chronic continuous nicotinetreatment change dopamine metabolism in the pre-frontal cortex but not in the dorsal striatum (87).

Again, pharmacological data suggest that these dif-ferences in dopaminergic modulation may be due to

differential subunit composition of the nicotinic recep-tors. Measures of agonist-induced dopamine release incortical versus striatal synaptosomes suggest that nico-tinic receptors in the cortex have a higher affinity fornicotine, but a quicker onset of desensitization afteracute nicotinic agonist treatment, than subcortical nic-otinic receptors (88). Hence, the different patterns ofnicotine-stimulated dopamine release in cortical andsubcortical structures may be due to different pharma-cological properties of nicotinic receptors in these re-gions, which in turn are likely determined by differentsubunit composition.

Differences in neural plasticity may also distinguishcortical and subcortical nicotinic receptors. Severalstudies suggest that cortical nicotinic receptor expres-sion is regulated by chronic nicotine treatment (89,90). Further, this change in expression appears to re-sult in electrophysiological activity of cortical neurons(91) and enhanced cortical dopamine release in re-sponse to nicotine challenge (86). These preclinicaldata suggest that chronic nicotine treatment affectscortical sensitivity to nicotine challenges to a greaterextent than treatment does for subcortical nicotinic re-ceptors. This is consistent with the hypothesis thatschizophrenia is associated with a dissociation of cor-tical-subcortical dopamine activity (53). Perhapsschizophrenic individuals smoke to stimulate cortical

activity without altering subcortical activity.Nicotine-Glutamate Interactions

The interaction of nicotine and glutamate is muchless well characterized than nicotine-dopamine interac-tions, but evidence supports a facilitating role for nico-tine in glutamatergic neurotransmission (92, 93). Nic-otine appears to enhance fast glutamatergic synaptictransmission in the cortex, and this phenomenon islikely mediated by a direct effect on nicotinic receptors(92). Recent evidence suggests that this may be more

specifically regulated by 7-subunit-containing nico-tinic receptors, since the nicotine-induced increase inglutamate levels in the hippocampus is inhibited by -bungarotoxin (93). This effect on hippocampal gluta-mate release may underlie the important set of findingsconcerning sensory gating abnormalities in schizophre-nia. As mentioned earlier, persons with schizophrenia

have abnormalities in prepulse inhibition (94). In nor-mal subjects, the second P50 wave associated with thisparadigm is diminished, but in subjects with schizophre-nia it is not (95). Recently, this gating abnormality hasbeen linked to the gene encoding the 7 subunit of thenicotinic receptor (44). Further, it has been hypothesizedthat this sensory gating phenomenon is mediated, atleast in part, by the hippocampus and associated ana-tomical structures (96). Since 7 nicotinic receptors arerelatively abundant in the hippocampus, Freedman et al.(96) examined -bungarotoxin binding in the postmor-tem hippocampus of schizophrenic and matched controlsubjects and found a decrease in binding in the subjectswith schizophrenia.

To explore this phenomenon further, a rodent modelhas been developed that uses evoked potential record-ings to measure the N40 wave that appears to corre-spond to the P50 wave in humans (97). This wave ap-pears to be localized to CA3 and CA4 pyramidalneurons of the hippocampus. The ability to gate audi-tory sensory information appears to rely on increasedinhibitory input to these neurons resulting from thefirst tone (97). It is interesting to note that this partic-ular subfield receives extensive cholinergic innerva-tion. In fact, lesions of the cholinergic fibers projectingto the hippocampus diminish the gating response, andnicotine treatment can, in turn, normalize gating in le-sioned animals (98). Further, either -bungarotoxin

treatment or 7 subunit antisense oligonucleotide treat-ment can disrupt sensory gating (97). Both treatments,in effect, serve to decrease 7-subunit-containing recep-tor activity, strongly suggesting a role for 7-subunit-containing receptors in this electrophysiological phe-nomenon. One model posits that the first sound acti-vates 7-subunit-containing nicotinic receptors, and thisin turn facilitates glutamate release (97). Subsequentlyactivated glutamate receptors located on GABA-ergicneurons then cause GABA release, which then inhibitspyramidal neurons in the CA3-CA4 subfields of the hip-pocampus and dampens response to the second stimulus(97). The role of glutamate in this model suggests thatnicotine-glutamate interactions in the hippocampus maybe critical to the process of sensory gating and could be asite of neurochemical dysregulation in schizophrenia. Itmay well be that smoking is an attempt to self-medicatethis physiological deficit in schizophrenia.

DISCUSSION

Nicotine treatment modulates both dopaminergicand glutamatergic neurotransmission, and these effectsare specific both to brain region and functional system.


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These differences may be due to the unique aspects ofthe circuitry of the nigrostriatal and mesocorticolimbicdopamine systems. It has been proposed that the cor-tico-striato-pallido-thalamic circuit links glutamater-gic and dopaminergic activity in limbic areas (54, 55)(figure 2). Such a circuit model may help to clarify themodulatory effects mediated by nicotinic receptors.

Glutamatergic corticostriatal neurons presynapticallyinnervate dopaminergic projections to the striatum.Neurons in the striatum that receive this innervationproject to the globus pallidus, which projects back toboth the midbrain (by way of the subthalamic nucleus)and the thalamus. The thalamus projects back to thecortex, creating several integrated circuits (54, 55).Any disruption in glutamatergic or dopaminergic ac-tivity may potentially disinhibit thalamic outflow,which would then alter cortical activity.

The dissociation of cortical-subcortical dopaminer-gic activity that is proposed to be related to psychoticsymptoms in schizophrenia may be viewed in the con-text of this model (53) and provides a role for nicotinic

receptors to modulate, and potentially normalize, thisdisturbance. The negative symptoms of schizophreniaseem to be associated with cortical hypoactivity, whilethe positive symptoms appear to be associated withsubcortical dopaminergic hyperactivity (53). Animalmodels of cortical hypoactivity demonstrate concomi-tant alterations in subcortical activity, which can benormalized by nicotine treatment (99). This suggeststhat nicotine, through increased glutamatergic trans-mission in the cortex, can affect striatal dopaminelevels and provides direct evidence for a complex inter-action of nicotine with both dopaminergic and gluta-matergic systems (100) (figure 3).

Dopamine is the neurotransmitter most often associ-ated with the pathophysiology of schizophrenia, butconverging lines of evidence also implicate glutamater-gic dysfunction in the disorder. Nicotine appears tomodulate the function of both of these neurotransmit-ter systems, suggesting that this modulation may un-derlie some of the clinical findings of a high prevalenceof nicotine use among individuals with schizophrenia.In general, increases in dopamine levels in cortical re-gions appear to be more sensitive to chronic nicotinetreatment than those in subcortical regions, which maybe associated with a potential correction of the corti-cal-subcortical dissociation of dopamine activity puta-tively associated with schizophrenia. In addition, themesocorticolimbic dopaminergic system, which ismost often associated with psychotic symptoms, ap-pears to be much more sensitive to the effects of nico-tine than the extrapyramidal motor system, lendingsupport to a hypothesis of self-medication of psychoticsymptoms for nicotine use in schizophrenia. The lesswell characterized interaction between nicotinergicand glutamatergic systems suggests that nicotine treat-ment is associated with increased glutamatergic activ-ity in limbic regions implicated in schizophrenia, par-ticularly the frontal cortex and hippocampus. Thehypofrontality associated with schizophrenia, as well

as the auditory gating lesions in schizophrenic subjects,may be partially normalized by nicotine treatmentthrough a glutamatergic mechanism.

The clinical and epidemiologic observations of ahigh rate of smoking among persons with schizophre-nia has led to greater understanding of the possible in-teractions between nicotines effects and signs and

symptoms of schizophrenic illness. Considerable clini-cal evidence supports the contention that nicotine ex-posure, through smoking, and schizophrenia may havea pathophysiological link. The neuronal nicotinic re-ceptors present considerable pharmacodynamic com-plexity and regional specificity, with implications fordopaminergic and glutamatergic cross-regulation. Ourunderstanding of these relationships, however, is farfrom complete. We suggest that preclinical and clinicalinvestigations of schizophrenia and nicotine addictioncan be more profitably linked across disorders to ex-tend our understanding of these conditions as both in-dividual and commonly comorbid phenomena. In ad-dition, understanding how and why schizophrenic

persons use nicotine to self-medicate symptoms mayalso lead to the development of new treatments forboth schizophrenia and nicotine dependence.

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Nicotine and schizophrenia