Cortical cholinergic transmission and cortical information processing in schizophrenia.

Abstract

Models of the neuronal mediation of psychotic symptoms traditionally have focused on aberrations in the regulation of mesolimbic dopaminergic neurons, via their telencephalic afferent connections, and on the impact of abnormal mesolimbic activity for functions of the ventral striatum and its pallidal-thalamic-cortical efferent circuitry. Repeated psychostimulant exposure models major aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. Based on neuroanatomical, neurochemical, and behavioral data, the hypothesis that an abnormally reactive cortical cholinergic input system represents a necessary correlate of a sensitized mesolimbic dopaminergic system is discussed. Moreover, the abnormal cognitive mechanisms that contribute to the development of psychotic symptoms are attributed specifically to the aberrations in cortical cholinergic transmission and to its consequences on the top-down regulation of sensory and sensory-associational input functions. Experimental evidence from studies demonstrating repeated amphetamine-induced sensitization of cortical cholinergic transmission and the ability of antipsychotic drugs to normalize the activity of cortical cholinergic inputs, and from experiments indicating the attentional consequences of manipulations that increase the excitability of cortical cholinergic inputs, supports this hypothesis. Relevant human neuropathological and psychopharmacological data are discussed, and the implications of an abnormally regulated cortical cholinergic input system for pharmacological treatment strategies are addressed. Given the role of cortical cholinergic inputs in gating cortical information processing, even subtle changes in the regulation of this cortexwide input system that represent a necessary transsynaptic consequence of sensitized mesolimbic dopaminergic transmission profoundly contribute to the neuronal mediation of psychotic symptoms.

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Cortical Cholinergic Transmission and Cortical Information
Processing in Schizophrenia
Martin Sarter, Christopher L. Nelson, and John P. Bruno
Send reprint requests to Dr. M. Sarter, Department of Psychology,
University of Michigan, 525 E. University Avenue, Ann Arbor,
MI 48109-1109; e-mail: msarter@umich.edu.
Models of the neuronal mediation of psychotic symptoms
traditionally have focused on aberrations in the regulation
ofmesolimbicdopaminergicneurons,viatheirtelencephalic
afferent connections, and on the impact of abnormal meso-
limbic activity for functions of the ventral striatum and its
pallidal-thalamic-cortical efferent circuitry. Repeated psy-
chostimulant exposure models major aspects of the sensi-
tized activity of ventral striatal dopaminergic transmission
that is observed in patients exhibiting psychotic symptoms.
Based on neuroanatomical, neurochemical, and behavioral
data,thehypothesisthatanabnormallyreactivecorticalcho-
linergic input system represents a necessary correlate of
a sensitized mesolimbic dopaminergic system is discussed.
Moreover, the abnormal cognitive mechanisms that contri-
butetothedevelopmentofpsychoticsymptomsareattributed
specifically to the aberrations in cortical cholinergic trans-
mission and to its consequences on the top-down regulation
ofsensoryandsensory-associationalinputfunctions.Exper-
imental evidence from studies demonstrating repeated am-
phetamine-induced sensitization of cortical cholinergic
transmission and the ability of antipsychotic drugs to nor-
malize the activity of cortical cholinergic inputs, and from
experiments indicating the attentional consequences of
manipulations that increase the excitability of cortical cho-
linergic inputs, supports this hypothesis. Relevant human
neuropathologicalandpsychopharmacologicaldataaredis-
cussed,andtheimplicationsofanabnormallyregulatedcor-
ticalcholinergicinputsystemforpharmacologicaltreatment
strategiesareaddressed.Giventheroleofcorticalcholiner-
gicinputsingatingcorticalinformationprocessing,evensub-
tlechangesintheregulationofthiscortexwideinputsystem
thatrepresentanecessarytranssynapticconsequenceofsen-
sitized mesolimbic dopaminergic transmission profoundly
contributetotheneuronalmediationofpsychoticsymptoms.
Keywords: Schizophrenia/cortex/acetylcholine/nucleus
accumbens/dopamine/attention
This article discusses the role of the cortical cholinergic
input system in the mediation of schizophrenia symp-
toms. Neuropathological data suggesting an abnormal
regulation of the cortical cholinergic input system in
schizophrenia remain rare and inconclusive, mostly be-
cause dynamic alterations in the activity of cholinergic
neurons cannot be readily revealed by neuropathological
assessments of the activity of non-rate-limiting enzymes
of cholinergic transmission (e.g., choline acetyltransfer-
ase, acetylcholine esterase; Haroutunian et al. 1994; Pow-
chik et al. 1998; Mancama et al. 2003). However,
neuropathological studies documented a decrease in
the density and expression of muscarinic receptors in
the cortex of schizophrenia patients (Crook et al. 2001;
Hyde and Crook 2001). Recently, Raedler et al.
(2003), using [123I]iodoquinuclidinyl benzilate single
photon emission computed tomography, confirmed the
decreasein muscarinic receptorsin unmedicatedpatients.
Several mechanisms could account for the downregula-
tion of muscarinic receptors; it could, for instance, be
a consequence of abnormally high levels of extracellular
acetylcholine (ACh).
Suggestions about the cholinergic system’s involve-
ment in schizophrenia have also been derived from psy-
chopharmacological studies (e.g., Davis et al. 1978).
Tandon and colleagues (Tandon and Greden 1989; Tan-
don et al. 1999) proposed that cholinergic hyperactivity
mediates negative symptomatology, including atten-
tional impairments. Their hypothesis corresponds with
many lines of evidence discussed below, including the
suggestion that cortical cholinergic (re)activity is partic-
ularly high during psychotic exacerbations and that the
activity of the cholinergic system covaries with perturba-
tions in dopaminergic activity. Tandon and colleagues’
focus on the mediation of negative symptoms by the cho-
linergic system has been corroborated by their findings
on the effects of acutely administered cholinergic drugs
(e.g., Tandon et al. 1993). However, long-term exposure
to cholinomimetic drugs may result in the manifestation
of psychotic symptoms. Evidence in support of this state-
ment remains necessarily anecdotal, but several cases of
accidental chronic exposure to cholinesterase inhibitors
(Gershon and Shaw 1961; Bowers et al. 1964; Karczmar
1981) indicated that persistent, abnormal increases in ex-
tracellular ACh levels are sufficient to produce or exac-
erbate psychosis. Furthermore, the symptoms of these
patients were—as predicted by the model described
below—treated successfully by antipsychotic drugs.
Schizophrenia Bulletin vol. 31 no. 1 pp. 117–138, 2005
doi:10.1093/schbul/sbi006
Advance Access publication on February 16, 2005
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The widespread abuse of anticholinergic drugs (e.g.,
trihexyphenidyl, benztropine) by schizophrenia patients,
who report a wide spectrum of subjective and functional
benefits from taking these drugs (Fisch 1987; Wells et al.
1989), also provides indirect support for the idea that at-
tenuation of an overly active or reactive cholinergic sys-
tem mediates beneficial effects. However, the degree to
which such positive effects can be objectified remains un-
settled (Johnstone et al. 1983; Strauss et al. 1990), as do
the functions of smoking and the status of nicotine recep-
tors in schizophrenia (Salokangas et al. 1997; Adler et al.
1998; Dalack et al. 1998).
Collectively, the clinical and neuropathological evi-
dence concerning the role of the cholinergic system in
schizophrenia is limited for several reasons, including,
as already mentioned, the absence of methods available
to document dynamic changes in the regulation of cho-
linergic neurons in the human brain (see also Heimer
2000). Emerging tracers for the imaging of cholinergic
receptors and aspects of cholinergic transmission in the
human brain (Mach et al. 1997; Mulholland et al.
1998; Nishiyama et al. 2000; Tsukada et al. 2001) are
likely to pave the way for more direct and informative
assessments of the status of cortical cholinergic transmis-
sion in schizophrenia patients.
Sensitization of Mesolimbic Dopaminergic Neurons and
Regulation of Cortical Cholinergic Inputs
SensitizedMesolimbicDAinSchizophrenia.
esis that abnormal regulation of ventral striatal,
specifically nucleus accumbens (NAC), dopaminergic
transmission represents a neuronal hallmark of schizo-
phrenia has been substantiated in recent years. Most
etiologic scenarios agree that the mesolimbic hyperdopa-
minergic state in schizophrenia is a result of developmen-
tal abnormalities in telencephalic circuits that cause
a dysregulation of midbrain dopaminergic neurons
(Weinberger and Lipska 1995; O’Donnell and Grace
1998; Grace 2000; Laruelle 2000; Lewis and Levitt 2002).
Imaging studies demonstrated increased amphet-
amine-induced (AMPH-induced) displacement of dopa-
mine (DA) D2 receptor ligands in schizophrenia patients,
suggestingasensitizedstriataldopaminergicinputsystem
(Breier et al. 1997; Laruelle and Abi-Dargham 1999; Lar-
uelle et al. 1999). Although the interpretation of the
mechanisms mediating the AMPH-induced displacement
of D2 ligands is not without controversy (Tsukada et al.
1999),theuseofAMPHinthesestudiescorrespondswith
the psychotogenic effects of repeated exposure to AMPH
and other psychostimulants in humans and in animal
models of schizophrenia. Alternatively, the risk for psy-
chostimulant addiction represents a corollary of schizo-
phrenic neuropathology (e.g., Segal et al. 1981; Robinson
andBecker1986;LeDucandMittleman1995;Lieberman
Thehypoth-
et al. 1997; Yui et al. 1999a; Castner et al. 2000; Laruelle
2000).
A hyperactive dopaminergic system in schizophrenia
patients can be demonstrated even in never-medicated
patients; such demonstration requires the presence of
psychotic symptoms (Laruelle et al. 1996, 1999; Strakow-
ski et al. 1997; Abi-Dargham et al. 1998; Laruelle and
Abi-Dargham 1999; Laruelle 2000; Seeman and Kapur
2000). Patients with first episode manic or schizophrenic
psychosis did not exhibit increased responses to a second
dose of amphetamine, suggesting that they already
exhibited a maximally sensitized dopaminergic system
(Strakowski et al. 1997). A sensitized mesolimbic DA sys-
tem has been hypothesized to be a necessary component
of the neuronal circuits mediating the expression of pos-
itive symptoms (Robinson and Becker 1986; Lieberman
et al. 1997; Yui et al. 1999a; Laruelle 2000).
The relationship between the positive symptoms of
schizophrenia and dopaminergic inputs to cortical areas
is less clear (e.g., Davis et al. 1991). Aberrations in the
functions of dopaminergic inputs to the prefrontal cortex
(PFC), including reductions in the density of DA D1
receptors (Okubo et al. 1997) and increases in DA syn-
thesis (Lindstrom et al. 1999), have been extensively dis-
cussed as representing the primary mediator of the
cognitive impairments of schizophrenia (Murphy et al.
1996a, 1996b; Goldman-Rakic and Selemon 1997; Zahrt
et al. 1997). Moreover, and more central to the present
hypothesis, abnormalities in prefrontal neurotransmis-
sion, possibly in interaction with structural abnormalities
of the PFC in schizophrenia patients (e.g., Lewis et al.
1999; Gluck et al. 2002), contribute via corticofugal pro-
jections to the abnormal regulation of striatal, including
NAC, DA transmission (e.g., Deutch 1993; Bertolino
et al. 1999; Carr et al. 1999; Moore et al. 1999b; Soares
and Innis 1999; Finlay 2001). Grace (1993) proposed that
the primary consequence of the defective regulation of
NAC DA afferents in schizophrenia is a decrease in tonic
DA release associated with anincrease in phasic, activity-
related DA release, possibly due in part to reduced local
autoinhibitory mechanisms (Grace 1993; Flaum and
Schultz 1996; O’Donnell and Grace 1998; Moore et al.
1999b).Chronictreatmentwithantipsychoticdrugsishy-
pothesized to normalize DA transmission by producing
a depolarization blockade (Grace et al. 1997; Grace
2000) that, in the case of atypical antipsychotic drugs,
has been proposed to be selective for the limbic A10
DA neurons (Chiodo and Bunney 1983).
Thus, the available evidence points to the NAC, par-
ticularly its shell region, as the critical component of ab-
normally regulated neuronal circuits mediating the
expression of positive symptoms (O’Donnell and Grace
1998),oreventheaberrationsofconsciousness,inschizo-
phrenia (Gray 1995). Grace and coworkers, as well as
Grayandothers,havefocusedonNAC-ventralpallidal—
mediodorsalthalamic—prefrontalconnections to
M. Sarter et al.
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conceptualize the consequences of dysregulation of NAC
information flow for cortical information processing (see
alsoO’Donnelletal.1997).Aswillbediscussedbelow,the
NAC has even more direct and widespread consequences
oncorticalinformationprocessingbyregulatingtheexcit-
ability of the corticopetal cholinergic system that arises
from medial and ventral pallidal regions, specifically
from the nucleus basalis of Meynert, the substantia inno-
minata, and the horizontal nucleus of the diagonal band
(henceforth termed collectively ‘‘basal forebrain’’ [BF];
figure 1). Furthermore, the abnormal regulation of corti-
calcholinergicinputsishypothesizedtomediatetheatten-
tional abnormalities that contribute to the expression of
the positive symptoms of schizophrenia.
Transsynaptic
Activity.
a structure linking motivational processes with the initia-
tion of behavior, specifically with the selection of stimuli
withincentiveoraversiveproperties.Dopaminergicinputs
totheNAC,originatingintheventraltegmentalarea,con-
verge with telencephalic (glutamatergic) projections on
medium spiny NAC efferents (Sesack and Pickel 1990;
Wu et al. 1993; Taber and Fibiger 1995; Finch 1996;
Whitelaw et al. 1996; Blaha et al. 1997; Floresco et al.
1998; Mulderet al.1998; Youet al. 1998).This interaction
is generally considered to be critical for the selection of
stimuli to act as conditioned reinforcers and to guide in-
strumental behavior (Cador et al. 1989, 1991; Everitt et al.
1989; Salamone 1994; Brown and Bowman 1995). Fur-
thermore, the degree to which such stimuli control behav-
ioral activity has been hypothesized to be a function of
NAC dopaminergic activity (Schultz et al. 1997; Young
et al. 1998).
The regulation of NAC output neurons by NAC do-
paminergic inputs is complex and depends strictly on
interactions with NAC glutamatergic inputs from telen-
cephalic regions (Burns et al. 1994; Taber and Fibiger
1997). O’Donnell (1999) stressed that the effects of DA
on NAC output neurons cannot be simplified as excit-
atory or inhibitory but depend on whether these neurons
Regulation ofCortical Cholinergic
The NAC has been traditionally discussed as
Fig. 1. Schematic and selective representation of the circuitry
involved in the dysregulation of cortical cholinergic (ACh, in red)
inputs, arising from the BF, in schizophrenia. Note.—ACh =
acetylcholine; BF = basal forebrain; DA = dopamine; GABA =
c-aminobutyric acid; GLU = glutamate; MD = mediodorsal
thalamic nucleus; NAC = nucleus accumbens; PFC = prefrontal
cortex; VTA = ventral tegmental area. Most etiological scenarios
suggestthat, asa resultof
dysmorphogenesis, an abnormal telencephalic regulation of the
activity of mesolimbic neurons (via cortical GLU projections, in
black) mediates the expression of the mostly positive symptoms
of schizophrenia. The mesolimbic dopaminergic system refers
primarily to the dopaminergic neurons that arise from the VTA
and project to the NAC and the PFC. Evidence indicates that, in
acute schizophrenia patients, mesolimbic dopaminergic neurons
exhibit the characteristics of a sensitized system, and this aspect
of the disease is modeled by the effects of psychostimulant
sensitization. There is also a mesoaccumbens GABAergic
pathway that is likely to be affected by abnormal telencephalic
inputs (Carr and Sesack 2000), but the regulation of NAC signal
transmission by GABAergic inputs is not well known. The
GABAergic projection from the NAC to the BF (in blue)
represents the major although not the exclusive pathway by which
the effects of an abnormally regulated mesolimbic dopaminergic
system are imported to the BF (e.g., not shown are multisynaptic
circuits through amygdaloid regions that are likely to contribute
to BF dysregulation). As a result of abnormal BF afferent
activity, cortical cholinergic inputs are excessively reactive.
Pathological increases in cortical cholinergic transmission directly
impair sensory and associational input processing and disrupt
filtering capacity. Indirectly, and primarily as a result of an
abnormallyreactivecholinergic
orchestration of top-down mechanisms, normally designed to
optimize, in a modality-specific fashion, posterior cortical input
processing,is disrupted.Such
mechanisms is thought to impair source monitoring capabilities
(this function is symbolized by the thick curved arrows at the
figure’s top). The BF cholinergic projection to the MD is also
shown because, via this projection (and also possibly via
noncholinergic BF projections to the MD; e.g., Young et al. 1984;
Mogenson et al. 1987; Hreib et al. 1988), the MD’s projections to
the PFC (e.g., Sarter and Markowitsch 1984) may also be
abnormally regulated and thus further impair information
processing in the PFC. Additionally, the PFC directly innervates
BF neurons, and thus, pathological PFC activity augments the
abnormal regulation of the BF (Sarter and Bruno 2002). Finally,
developmentaltelencephalic
inputtothePFC,the
disruptionoftop-down
direct dopaminergic projections from the VTA to the BF (e.g.,
Gaykema and Zaborszky 1996; Zaborszky and Cullinan 1996)
and the MD (Beckstead et al. 1979; Cornwall and Phillipson
1988) are also likely to contribute directly and indirectly to the
abnormal regulation of the cortical cholinergic inputs, but data
specifying these dopamine-cholinergic interactions in the BF, or
thedopaminergic regulation
(Momiyama and Sim 1996; Lavin and Grace 1998). In general,
this scenario extends traditional models of schizophrenia that
have focused on the mesolimbic DA system and represents the
hypothesis that dysregulation of the cortical cholinergic input
system is the primary mediator of the impairments in cortical
information processing in schizophrenia, specifically of the
attentional abnormalities that contribute to the manifestation of
psychotic symptoms.
of MDefferents,are rare
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Cortical Acetylcholine and Schizophrenia

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exhibit a highly polarized resting membrane potential
(down state) or depolarized plateaus (up state) and on
the DA receptor subtypes activated (O’Donnell 1999).
In fact, D1 and D2 receptors mediate different effects
of DA on NAC output neurons, and these effects interact
with the state of these neurons (for review, see Nicola
et al. 2000). Moreover, prefrontal, hippocampal, and
amygdaloid projections to the NAC are differently mod-
ulated by DA D1 and D2 receptors (O’Donnell and
Grace 1996; Charara and Grace 2003). Finally, increases
in activity of DA NAC inputs are observed in association
with converging glutamatergic activity (Youngren et al.
1993; Darracq et al. 2001; Floresco et al. 2001a, 2001b,
2001c; Howland et al. 2002), suggesting that the modu-
latory function of DA is partly regulated by glutamater-
gic inputs to the NAC.
O’Donnell (1999) further suggested that DA activates
cell ensembles (possibly via gap junction modulation)
that then maintain an up state, thereby robustly enhanc-
ing the processing of telencephalic inputs by the NAC
(O’Donnell and Grace 1993; O’Donnell 1999). It is in-
triguing to extrapolate such a scenario to the consequen-
ces of psychostimulant sensitization, as the resulting
abnormally reactive DA activity in the NAC would be
expected to produce a more extensive and persistent for-
mation of such functional cell ensembles, thereby patho-
logically expanding the range and degree to which
telencephalic inputs are selected, and thus act as incentive
stimuli and control behavior. Abnormally reactive NAC
DAinputsmayalsosuppresstherelativecontributionsof
hippocampal and amygdaloid afferents to NAC func-
tioning, while allowing prefrontal throughput to domi-
nate the state of NAC outputs (Charara and Grace
2003). As will be discussed below, such a breakdown
in NAC functions is complemented and augmented by
abnormal increases in the reactivity of cortical choliner-
gic inputs.
The main efferent pathway of the NAC shell reaches
the ventral pallidum (Mogenson et al. 1983; Zahm and
Brog 1992; Zahm and Heimer 1993; Usuda et al. 1998;
Zahm et al. 1999) and appears to be largely GABAergic
(GABA is c-aminobutyric acid; Walaas and Fonnum
1980; Zaborszky and Cullinan 1992; Zahm and Heimer
1993). There is evidence for other types of NAC projec-
tions to the BF (e.g., Napier et al. 1995), but this anatom-
ical organization remains unsettled. NAC GABAergic
projections make direct contact with BF cholinergic neu-
rons(Inghametal.1988;Zaborszky1992;Zaborszkyand
Cullinan 1992). BF cholinergic neurons innervate practi-
cally all cortical areas and layers and thus gate all cortical
information processing (Mesulam 1990).
Neuropharmacological evidence supports the transsy-
naptic regulation of the excitability of BF corticopetal
(cholinergic) neurons by NAC GABAergic efferents.
For example, infusions of DA agonists into the NAC in-
crease firing rates of neurons in the BF (Yang and
Mogenson 1989), suggesting that DA, within the
NAC,inhibitstheGABAergicprojectiontotheBF.Kali-
vas and colleagues demonstrated that systemic adminis-
tration of AMPH decreases GABA efflux in the ventral
pallidum (Bourdelais and Kalivas 1990) and that the
effects of systemic apomorphine (a DA agonist) on BF
GABAefflux are potentiatedbya priordepletion offore-
brain DA (Bourdelais and Kalivas 1992; see also Mele
et al. 1998). Conversely, infusions of DA D1 and D2 re-
ceptor antagonists into the NAC increase GABA efflux
in ventral pallidal areas, which include the substantia
innominata and the nucleus basalis of Meynert (Ferre
et al. 1994; see also Yamamoto et al. 1994).
As would be predicted from the anatomical evidence in
support of a NAC efferent regulation of GABAergic ac-
tivity in the BF, manipulations of NAC neurotransmis-
sionalter the regulation
transmission. For example, increases in cortical ACh ef-
flux, produced by the systemic administration of a nega-
tive GABA modulator, the benzodiazepine receptor
(BZR) partial inverse agonist FG 7142, are blocked by
systemic administration of haloperidol, or intra-NAC
infusions of haloperidol or the D2 receptor antagonist
sulpiride (Moore et al. 1999a). Although the use of
a BZR partial inverse agonist to stimulate cortical
ACh complicates the interpretation of the results, these
and more recent findings (below) correspond with the hy-
pothesis that NAC DA receptor stimulation inhibits
GABAergic outputs to BF cholinergic neurons and
that infusions of D2 antagonists into the NAC reinstate
the GABAergic inhibition of corticopetal cholinergic
neurons. The finding that FG 7142–induced increases
in medial prefrontal cortical ACh efflux were not atten-
uated by local cortical perfusion of DA receptor antag-
onists (Moore et al. 1999a) corresponds with the
assumption that the effects of systemically administered
DA antagonists on cortical ACh efflux primarily involve
NAC mechanisms (see also Bianchi et al. 1979; Day et al.
1994).
Mesolimbic projection systems regulate the excitability
of BF neurons via additional multisynaptic circuits, in-
cluding the bidirectional connections between the meso-
limbic DA neurons and the amygdala (Fallon et al. 1978;
Kelley et al. 1982; Wright et al. 1996), and the amygdala
and the BF (e.g., Jolkkonen et al. 2002), and the direct
projections of the ventral tegmentum to the BF (Gay-
kema and Zaborszky 1996; Momiyama and Sim 1996;
Zaborszky and Cullinan 1996; Smiley et al. 1999).
Thus, in addition to the route via the NAC, telencephalic
pathology contributes to the dysregulation of the BF cor-
ticopetal system via multiple neuronal routes (figure 1).
Within the BF, GABAergic activity has been demon-
strated to affect profoundly the excitability of corticope-
talcholinergicprojections.
substantiated the regulation of cortical ACh efflux
by BF GABAergic inputs by demonstrating that the
ofcorticalcholinergic
Our previous studies
120
M. Sarter et al.

Page 5

systemic or intra-BF administration of positive and neg-
ative GABA modulators (BZR agonists and inverse ago-
nists) bidirectionally regulates cortical ACh efflux (Sarter
and Bruno 1994; Bruno and Miller 1995).
As the GABAergic efferents of the NAC are contacted
byglutamatergicafferents (Meredith1999),NACmanip-
ulations of glutamatergic transmission are expected to af-
fect cortical ACh efflux. A series of experiments
demonstrated that blocking NMDA or AMPA/kainate
ionotropic glutamate receptors in the shell region of
the NAC resulted in marked and lasting increases in me-
dial prefrontal basal ACh release (Neigh-McCandless
et al. 2002). It appears unlikely that decreases in BF
GABAergic activity were solely responsible for these ro-
bust increases in basal ACh efflux; rather, direct stimu-
lation of BF cholinergic neurons, via multiple afferent
routes, including ventral tegmental (e.g., Momiyama
and Sim 1996) and amygdaloid connections (see above;
see also Givens and Sarter 1997), convergewith decreases
in BF afferent GABAergic activity to yield the observed
increases in cortical ACh release (figure 1). Although the
determination of the exact neuronal mechanisms mediat-
ing these effects requires more experimentation and
may differ from the mediation of the effects of systemic
or intra-NAC psychostimulants (Mele et al. 1998),
these data support the notion that alteration of NAC
output profoundly changes the regulation of cortical
ACh efflux.
Behavioral studies concerning DA-GABAergic, NAC-
BF interactions are rare. Patel and Slater found that the
ability of NAC infusions of DA agonists to stimulate lo-
comotion is attenuated by infusions of muscimol into the
ventral pallidal area (Patel and Slater 1988; see also
Mogenson et al. 1983; Sarter et al. 1990; Mele et al.
1998).Likewise,Swerdlow
1990a, 1990b) demonstrated that infusions of GABA
into the ventral pallidum reverse the disruption of pre-
pulse inhibition in the acoustic startle test that results
from infusions of DA into the NAC. Pierce and Kalivas
(1997) indicated that psychostimulant-sensitized motor
activity is attenuated by infusions of muscimol into the
ventral pallidum. These findings support the hypothesis
that the functional consequences of NAC DA receptor
stimulation are mediated in part by a decrease in
GABAergic output to the BF (see also Kitamura et al.
2001; figure 1).
Collectively, the available data correspond well with
the hypothesis that NAC DA contributes potently to
the regulation of BF corticopetal cholinergic neurons.
Therefore, because abnormal regulation of NAC neuro-
transmission is part of the circuitry mediating the expres-
sion of psychotic symptoms (see above), the associated
dysregulation of BF corticopetal cholinergic neurons is
expected to represent an essential component of this cir-
cuitry (see also Heimer 2000). As will be discussed next,
the effects of psychotogenic treatments on the regulation
andcolleagues(1984,
of cortical cholinergic transmission further support this
hypothesis.
Increases in Cortical ACh Efflux by Psychotogenic
Manipulations
Repeated, intermittent exposure to AMPH represents
a robust psychotogenic manipulation and, in fact, is suf-
ficient to initiate and maintain schizophrenic symptom-
atology (Bell 1965; Ellinwood 1967; Segal et al. 1981;
Robinson and Becker 1986; Lieberman et al. 1990,
1997; Flaum and Schultz 1996). In humans, AMPH-in-
duced psychosis involves obsessive and compulsive be-
havioral and cognitive activities, hallucinations, and
paranoid delusions (Rylander 1972; Ellinwood et al.
1973; Segal and Janowski 1978). As discussed above, sen-
sitization of the mesolimbic dopaminergic system repre-
sentsamajor consequence
administration (see also Pierce and Kalivas 1997). Based
on the transsynaptic regulation of BF corticopetal cho-
linergic projections by the NAC (discussed above), re-
peated psychostimulant
predicted to also affect the regulation of cortical cholin-
ergic transmission.
We investigated the effects of repeated AMPH admin-
istration on cortical ACh release using in vivo microdial-
ysis in rats (Nelson et al. 2000). AMPH was administered
once every other day for five total administrations ini-
tially. AMPH-induced increases in cortical ACh efflux
were not immediately affected by this pretreatment reg-
imen. However, administration of AMPH 19 days after
the initial regimen resulted in significant augmentation
of, or sensitization of, the increase in cortical ACh efflux
(for details and control experiments, see Nelson et al.
2000). Further studies demonstrated that the augmented
increase in cortical ACh efflux remained a reliable effect
of repeated AMPH exposure, even when AMPH ‘‘chal-
lenges’’ were given following longer time intervals after
the completion of the initial treatment regimen (Nelson,
Sarter, Bruno, unpublished results).
The available, although limited, evidence on the effects
of other psychotogenic manipulations supports the gen-
eralideathatincreasesincorticalACheffluxrepresentan
essential component of the neuronal effects of such
manipulations.Administrationofthepsychotogenicnon-
competitive NMDA receptorantagonistketamine (Krys-
tal et al. 1994; Lahti et al. 1999; Newcomer et al. 1999)
produces large (>250%) increases in cortical ACh efflux
(Nelson et al. 2002a). However, in contrast toAMPH, re-
peated exposure to ketamine does not seem to alter the
increase in ACh efflux observed following the initial ke-
tamine exposure (Nelson et al. 2002a). Administration of
phencyclidine (PCP) likewise increases cortical ACh ef-
flux,butthiseffectdoesnotchangeasaresultofpretreat-
ment with PCP (Jentsch et al. 1998a). These data indicate
interestingandunsettleddissociationsbetweentheeffects
of repeatedAMPH
administrationhas been
121
Cortical Acetylcholine and Schizophrenia