Brain Research Reviews 31 2000 330–341
Gating of information flow within the limbic system and the
pathophysiology of schizophrenia1
Anthony A. Grace)
Departments of Neuroscience and Psychiatry, UniÕersity of Pittsburgh, 458 Crawford Hall, Pittsburgh, PA 15260, USA
Accepted 30 June 1999
Although first thought of as a dopaminergic disorder, there is little direct evidence to support a primary pathology in the dopamine
system as the etiological factor in schizophrenia. In contrast, evidence is amassing in support of a cortical disturbance in this disorder; one
consequence of which is a disruption in the cortical regulation of subcortical dopamine systems. Our studies show that the hippocampus
plays a major role in this interaction, in that, along with the dopamine system, it provides a gating influence over information flow from
the prefrontal cortex at the level of the nucleus accumbens. Moreover, chemically-induced disruption of the development of the
hippocampus and entorhinal cortex were found to lead to pathophysiological changes in these interactions in the limbic system of adult
rats. Therefore, schizophrenia is proposed to be a developmentally-related disorder, in which disruption of the hippocampal influence over
the limbic system during ontogeny results in a pathological alteration of corticoaccumbens interactions in the adult organism. q2000
Elsevier Science B.V. All rights reserved.
Keywords: Schizophrenia; Nucleus accumbens; Prefrontal cortex; Hippocampus; Amygdala; Dopamine; Glutamate
1. Introduction — the dopamine hyphothesis of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Evidence for cortical involvement in the pathophysiology of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Relevance of the nucleus accumbens to schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. The cellular basis for hippocampal-PFC-DA interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. PFC innervation of accumbens neurons in vitro — modulation by dopamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Gating of PFC afferent input within the accumbens by the hippocampus and the amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Potential role for DA in modulating synaptic interactions in the nucleus accumbens — the tonicrphasic model of DA system regulation . . . . .
6. Synaptic plasticity and the impact of neonatal hippocampal lesions on limbic system function in the adult. . . . . . . . . . . . . . . . . . . . . .
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
)Tel.: q 1-412-624-4609; Fax: q 1-412-624-9198; E-mail: Grace@brain.bns.pitt.edu
1Published on the World Wide Web on 17 November 1999.
0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S0165-0173 99 00049-1
A.A. GracerBrain Research ReÕiews 31 2000 330–341
Introduction—the dopaminehypothesis of
For years, investigators have examined the human brain
in a search for the etiology of schizophrenia using phar-
macological and anatomical approaches. Nonetheless, only
recently have these studies begun to yield information of
relevance to advancing our understanding of this complex
disorder. One of the initial models of schizophrenia that
has been fruitful in this quest relates to the involvement of
the neurotransmitter dopamine DA . This model, which
has become known as the DA hypothesis of schizophrenia,
is based on several pieces of compelling evidence. Among
these is the finding that drugs that increase DA release
within the brain will mimic several aspects of the
schizophrenic psychosis in normals, and will exacerbate
the psychotic symptoms in patients with schizophrenia
5,59,113 . Moreover, all drugs currently in use that are
effective at treating schizophrenia block DA receptors
within the brain 22,29,106 . This evidence led to the
hypothesis that schizophrenia may be due to a hyper-
dopaminergic state 120 .
Upon closer examination, the simplest form of the DA
model proved to be inadequate to account for the patho-
physiology of this complex disorder. Thus, although drugs
such as amphetamine will mimic at least the paranoid type
of schizophrenia and exacerbate positive symptoms 3,4 ,
this is accompanied by a substantial increase in DA
turnover in the brain i.e., up to 35-fold in animal studies,
112 . In contrast, despite substantial efforts, there is little
evidence for a marked increase in DA turnover in the
brains of patients with schizophrenia 11,99,119 . Further-
more, although antipsychotic drugs will rapidly block DA
receptors within minutes of their administration 105 and
can readily reverse amphetamine psychosis, the maximal
therapeutic effects are not achieved in patients with
schizophrenia unless these drugs are administered for weeks
60 . This would not be consistent with a simple DA
receptor blocking action, since one would predict that the
maximal DA antagonism should be achieved with acute
administration, whereas after repeated treatment the induc-
tion of compensatory changes in the DA system e.g.,
receptor up-regulation, increase in DA synthesis, etc.
should offset the effects of the antipsychotic drug, necessi-
tating higher dose administration. In contrast, evidence
shows that once a therapeutic response is achieved, it is
not necessary to increase the dose of the antipsychotic
drug in order to maintain therapeutic efficacy.
One explanation for the requirement of repeated an-
tipsychotic drug administration in the treatment of
schizophrenia is the time-dependent induction of DA neu-
ron inactivation, known as depolarization block 19,49,50 .
Whereas such a condition may indeed down-regulate DA
system responsivity by preventing the DA neurons from
becoming activated by potentially pathological levels of
excitatory input 50 , it is clear that this treatment does not
restore the system to ‘normal’. Instead, antipsychotic
drug-induced depolarization block appears to be an offset-
ting deficit introduced into what may be an otherwise
normal DA system in order to compensate for the patho-
physiological insult in the brain of the schizophrenic
46,47 . This raises the question as to what is the primary
site of pathophysiology that can lead to such a pervasive
brain disturbance? This evidence may be derived from
more recent studies of metabolic activation and imaging
within the brain of the schizophrenic patient.
2. Evidence for cortical involvement in the pathophysi-
ology of schizophrenia
Several studies have suggested that, instead of being a
schizophrenia may instead represent a dysfunction in corti-
cal systems using the neurotransmitter glutamate. This was
founded on initial studies suggesting that the schizophrenia
patient exhibited a tonic decrease in activity within the
prefrontal cortex 9,20,39,72,73 , particularly in those pa-
tients with prominent deficit syndrome 116 . This condi-
tion was termed hypofrontality. However, more recent
investigations have provided contradictory evidence, sug-
gesting that hypofrontality does not exist in the brain of
the schizophrenia patient 53 . In contrast, the prefrontal
cortex of afflicted individuals tends to show a diminished
activation compared to controls 2,9 during tasks that
require prefrontal cortical activity, such as working mem-
ory tasks 45 . Indeed, the poor performance of schizophre-
nia patients on working memory tasks that require frontal
cortical involvement e.g., the Wisconsin Card Sort task,
37,44is accompanied by a failure to activate the PFC
metabolically 9 . Moreover, insults that disrupt the PFC in
human subjects are reported to produce a condition with
characteristics similar to that observed in the deficit state
of schizophrenia 83 . However, in spite of this evidence,
reports of gross structural disturbances of the PFC that are
of sufficient magnitude to disrupt behavior have not been
made in patients with schizophrenia 110,123 .
Evidence has accumulated to suggest that deficits in
other cortical regions may play a role in the pathophysiol-
ogy of schizophrenia. For example, studies of schizophre-
nia patients revealed morphological alterations within the
amygdala 6,100 as well as a decrease in metabolism in
limbic-related cortical areas that are connected reciprocally
with the amygdala 116 . In particular, disruptions of neu-
ronal function within the amygdala and anterior cingulate
cortex are proposed to encompass a particular set of
symptoms in schizophrenia, such as attentional deficits,
blunted affect, and the inability to respond appropriately to
social situations. These types of symptoms are analogous
to those that occur with lesions of the amygdala in non-hu-
man primates, and resemble the behavioral deficits ob-
served in humans with lesions of the anterior cingulate,
A.A. GracerBrain Research ReÕiews 31 2000 330–341
which is interconnected with the amygdala 33,63,101 .
There has also been recent evidence that implicates hip-
pocampal dysfunction in schizophrenia. Among this evi-
dence are reports of cellular organizational disturbances in
the hippocampus of schizophrenics 27,64 as well as a
decrease in hippocampal volume 15 that is particularly
prominent in the afflicted cohort of twins discordant for
schizophrenia 115 . However, in contrast to the patho-
physiological consequences that are observed upon phar-
macological manipulation of the DA system or the PFC,
lesions that involve the ventral hippocampus in adult ani-
mals does not produce a state that resembles the psy-
chopathological disturbances observed in schizophrenia.
In contrast, recent studies by Lipska, Weinberger and
colleagues suggest that the important variable with respect
to the pathophysiology of schizophrenia is the develop-
mental period during which the hippocampal pathology
takes place. Therefore, even though lesions of the ventral
hippocampal region performed in adult animals fails to
produce schizophrenia-like alterations in limbic system
function, disruption of this brain region in neonatal rats
causes these behavioral alterations to emerge after the rat
reaches the adult stage 74 . The behavioral alterations
produced by these neonatal ventral hippocampal lesions
include hyperlocomotion and increased responsiveness to
stress and amphetamine. Such responses resemble those
observed after prefrontal cortical lesions made in adult
animals 1,57,125 .
Why does a neonatal lesion within the hippocampal
structure lead to an emergence of dysfunction within the
prefrontal cortical-accumbens DA system in the adult? It is
not likely that these deficits are a direct result of hip-
pocampal damage, given that hippocampal lesions in adults
do not lead to these types of behavioral profiles. Thus, it is
not obvious how hippocampal pathology in the neonate
Žwhich otherwise has a higher capacity for compensatory
changes; 18 causes a transformation in adult corticoac-
cumbens-mediated behaviors. Among several explanations
is the possibility that the neonatal hippocampal damage
may trigger compensatory changes within systems that
depend on a normal hippocampal input. In fact, studies
have suggested that glutamatergic transmission is neces-
sary for the induction of several types of time-dependent
modifications to occur within dopaminergic systems
34,61 . Therefore, damage to the hippocampus in neonates
may induce a functional reorganization within the limbic
system as a means of compensating for this pathology.
3. Relevance of the nucleus accumbens to schizophrenia
Among the limbic structures that have been investi-
gated, the nucleus accumbens continues to attract the
interest of researchers studying the neurobiological bases
of schizophrenia for several reasons. With respect to neu-
roanatomy, the nucleus accumbens receives glutamatergic
afferent input from each of the cortical regions that have
been associated with schizophrenia, including the paleocor-
tex amygdala , archicortex hippocampus and neocortex
PFC 7,25,40,77,84,108 , in addition to a significant in-
put from the ventral tegmental area DA neuron population
8,122 . The nucleus accumbens neurons send projections
to the ventral pallidum 54 , which in turn sends efferents
to the thalamus, including a major projection to the
mediodorsal nucleus of the thalamus
mediodorsal thalamic nucleus is the region of the thalamus
that is interconnected with the PFC 118 , and is thought to
regulate its activity. The mediodorsal thalamus itself has a
dopaminergic innervation 8,28,52 , which we have shown
will facilitate oscillatory activity within this thalamic re-
gion 69 . The nucleus accumbens also exhibits substantial
alterations in response to repeated administration of an-
tipsychotic drugs, including intercellular dye coupling
88,95 , the expression of mRNA 78 , and the induction of
immediate early genes 32,103 . The selectivity of classical
and atypical antipsychotic drugs for these actions and the
delayed onset of these antipsychotic drug-induced re-
sponses is cited as evidence that the nucleus accumbens
may be a primary site of therapeutic action of antipsy-
chotic drugs 50 , given the temporal correspondence be-
tween these actions and the delayed therapeutic response
of schizophrenia patients to antipsychotic drug administra-
tion 60 .
67,128 . The
4. The cellular basis for hippocampal-PFC-DA interac-
As a way of integrating the above observations, current
models into the pathophysiology of schizophrenia suggest
that this disorder is not due to a primary pathology within
the dopaminergic system. Instead, an emerging concept is
that the DA system may be relatively normal, but is
subjected to a dysregulation as a consequence of the
abnormal control by cortical glutamatergic afferents, e.g.,
21,46 . We have examined the mechanisms that may
contribute to this type of pathological cortical modulation
of subcortical DA system function using correlated in vivo
and in vitro intracellular recording techniques. Using this
approach, we have assessed the functional interaction of
several of these major components believed to play a role
in the pathophysiology of schizophrenia.
4.1. PFC innerÕation of accumbens neurons in Õitro —
modulation by dopamine
DA appears to exert a multitude of actions within the
nucleus accumbens 117,127 . Among these actions are a
direct, potent depression of nucleus accumbens neuron
excitability 79,89 . Moreover, DA appears to also depress
excitatory afferent input arising from PFC, amygdala, and
hippocampus 86,98,126 . The interaction of DA with PFC
afferents is of particular interest, in that DA was found to
A.A. GracerBrain Research ReÕiews 31 2000 330–341
exert a tonic presynaptic inhibitory influence on PFC-
evoked responses on accumbens neurons, although the
pharmacological nature of this response was atypical 86 .
Specifically, we found that administration of the D2 ago-
nist quinpirole 1–20 mM to accumbens slices in vitro
attenuated the amplitude of cortical afferent stimulation-
evoked EPSPs in 40% of accumbens neurons tested. More-
over, the D2-specific antagonist sulpiride increased EPSP
amplitude in most of the cells tested. The response to
sulpiride suggested that the EPSP was inhibited by tonic
levels of DA in the tissue. This was supported by the
observation that, in slices obtained from DA-depleted ani-
mals, sulpiride failed to induce changes in the amplitude of
the EPSPs, whereas quinpirole produced a highly signifi-
cant suppression of EPSP amplitude in every cell tested.
These results indicate that DA modulates the response of
accumbens neurons to corticoaccumbens fiber stimulation
via D2 receptors. Furthermore, these D2 receptors appear
to be located presynaptically on the cortical afferent termi-
nals, since this action of DA was not accompanied by
changes in membrane potential, input resistance, or time
constant, and was not modified by changes in the mem-
brane potential. Although DA terminals have not been
found to synapse directly onto glutamatergic afferents,
ultrastructural studies show that these terminals land in
close proximity to each other on single dendritic spines of
accumbens neurons 109 . These data provide support for
the presence of a tonic basal level of D2 receptor stimula-
tion in the accumbens slice preparation.
In addition, stimulation of DA receptors and stimulation
of cortical afferent fibers were both found to exert potent
and regionally-selective modulation of the incidence of
dye coupling in the accumbens core and shell regions, as
well as in the dorsal striatum 85,90,94 . Furthermore, the
increase in dye coupling produced by cortical afferent
stimulation was found to be mediated by a nitric oxide-de-
pendent process 91 . This dye coupling is thought to
indicate the presence of electrical coupling mediated by
gap junctions between nearby neuronal dendrites. Intercel-
lular coupling is proposed to be an important mechanism
for modulation of neuronal interaction at the network level.
For this reason, it is significant that it can be modulated in
a regionally-selective manner by repeated administration
of antipsychotic drugs 88,96 or amphetamine 96,97 .
Therefore, DA was found to exert multidimensional ac-
tions within the nucleus accumbens that occur over several
levels of integration.
4.2. Gating of PFC afferent input within the accumbens by
the hippocampus and the amygdala
As described above, the PFC input to the accumbens
appears to be regulated presynaptically by the DA system.
The corticoaccumbens system is also subject to gating
influences by other afferents to the nucleus accumbens as
well. In particular, evidence garnered from in vivo intra-
cellular recording studies revealed that the hippocampus
exerts a potent modulatory control over PFC afferent
activation of neurons in this brain region. Thus, accumbens
neurons recorded intracellularly in vivo exhibited substan-
tial levels of spontaneous activity consisting of sponta-
neous EPSPs, plateau depolarizations, and spike discharge
87 . Moreover, the plateau depolarizations caused the
membrane potential of the accumbens neurons to alternate
between two clearly identifiable states: a hyperpolarized,
non-firing state and a depolarized state during which the
neuron fired action potentials Fig. 1 . Therefore, these
neurons exhibited a bistable steady-state membrane poten-
tial. This depolarization appears to be driven by afferents
from the hippocampus subiculum. Thus, although most of
the neurons in the nucleus accumbens exhibited excitatory
potentials in response to stimulation of the fornix, in cells
that exhibited spontaneous bistable states fornix stimula-
tion evoked a unique response. This response consisted of
either a long-lasting transition to the depolarized state or a
prolonged EPSPrplateau potential with a duration of 40–
60 msec followed by a repolarization. This could also be
readily induced by delivering a train of stimulus pulses to
the fornix. However, if the fimbriarfornix is transected,
none of the accumbens neurons recorded exhibited this
bistable membrane potential. Similarly, injection of the
local anesthetic lidocaine onto the fimbriarfornix induced
a reversible suppression of the bistable state 87 . There-
fore, the hippocampal subiculum appears to be the drive
that causes nucleus accumbens neurons to exhibit the
There is substantial evidence that the plateau depolar-
izations of the bistable state were driven by hippocampal
subicular afferents. First, there is known to be a substantial
glutamatergic innervation of the accumbens derived from
the fimbriarfornix that originates in the ventral subiculum
13,14,30,40,62 . This is consistent with the rapid excita-
tion observed upon stimulation of the fimbriarfornix,
which resembles responses obtained by ventral subicular
stimulation 13 , rather than the slower modulatory actions
that would be produced by activation of monoaminergic
afferents in the fimbriarfornix 107 . Furthermore, the
rhythmic activity of the plateau depolarizations resembles
hippocampal theta-like activity 71,87 . Finally, stimulation
of nearby structures e.g., thalamus evoke markedly dif-
ferent responses than those observed with fimbriarfornix
In contrast, stimulation of PFC afferents evoked only a
brief excitatory response that, in itself, exhibited a low
probability of triggering spike discharge in accumbens
neurons. In contrast, if a hippocampal stimulation-evoked
plateau discharge was evoked first, subsequent stimulation
of the PFC afferent readily evoked spike discharge in the
nucleus accumbens neuron. Thus, activation of the subicu-
lar input caused the bistable neuron to shift to a depolar-
ized state, during which PFC afferents are capable of
triggering spike discharge Fig. 1 . This interaction appears
A.A. GracerBrain Research ReÕiews 31 2000 330–341
Fig. 1. Hippocampal gating of information flow from the prefrontal cortex via modulation of nucleus accumbens neuronal activity. A In vivo intracellular
recording illustrating the bistable membrane state of neurons in the nucleus accumbens. The membrane potential of these neurons alternates between a
hyperpolarized, inactive state and a depolarized plateau during which action potentials are generated. Our studies revealed that the subiculum of the
hippocampus is responsible for driving the depolarized state in these neurons. Moreover, afferent input from the prefrontal cortex is capable of triggering
action potentials only when the accumbens neuron is in the depolarized state. B A model of hippocampal gating of prefrontal cortical input.
Spontaneously active prefrontal cortical cells filled circles provide afferent stimulation to each of the four nucleus accumbens neurons illustrated. In
contrast, a limited afferent input from the hippocampus one filled circle, dark arrow causes only one of the accumbens neurons to enter the depolarized
state. Only the accumbens neuron in this depolarized state is capable of passing prefrontal cortical information through to the ventral pallidum and on to
the thalamocortical system. In this way, the hippocampus opens a ‘gate’ in the accumbens to allow passage of only a subset of information arriving from
the prefrontal cortex.
therefore to act as a gate, in which the hippocampal input
is required to ‘arm’ the gate to respond to subsequent input
arriving from the PFC. This would thereby enable informa-
tion to flow from the PFC through the accumbens and
ventral pallidum, and on to activate thalamocortical cir-
cuits. In particular, such a system would enable the PFC to
activate afferents to the mediodorsal nucleus, thereby rein-
forcing activity within a loop circuit determined by the
This gate also is affected by drugs which are known to
be psychotomimetic agents. Thus systemic administration
of the D1 agonist SKF38393 combined with the D2 ago-
nist quinpirole was found to decrease the frequency at
which the membrane potential exhibited transitions to the
depolarized state i.e., from 1 Hz to 0.5 Hz; O’Donnell
and Grace, in preparation . In addition, systemic adminis-
tration of phencyclidine PCP caused a marked attenua-
tion of the spontaneous occurrence of depolarizing plateau
potentials. Moreover, this effect appears to be mediated via
an action outside of the subiculum, since direct injection of
PCP into the subiculum failed to attenuate the bistable
state 93 . Given that the bistable state is necessary for
gating of the PFC throughput in the nucleus accumbens,
this decrease in the bistable state frequency would result in
a functional blockade of prefrontal cortical throughput in
In addition to gating by the subiculum, we have exam-
ined the ability of the amygdala to gate PFC throughput in
the nucleus accumbens as well. Using in vivo intracellular
recordings, we found that stimulation of the amygdala
caused a brief depolarization of nucleus accumbens neu-
rons 87 . Moreover, if a stimulus train delivered to the
basolateral amygdala preceded stimulation of the PFC,
there was a facilitation in the probability of PFC stimula-
tion to evoke an action potential in accumbens neurons
81 . This potentiation was found to depend on the interval
A.A. GracerBrain Research ReÕiews 31 2000 330–341
Fig. 2. The accumbens is a site in which limbic structures have overlapping input with the dopamine system. In this model, the prefrontal cortex provides
multiple motor plans by which it drives goal-directed behavior. The most effective plan is then selected within the nucleus accumbens via the facilitatory
effects of hippocampal and amygdalar influences. This selection occurs via the ability of the hippocampus and amygdala afferents to facilitate the response
of accumbens neurons to the specific prefrontal cortical input chosen. Under normal conditions, the hippocampus selects behavioral output based on the
current context of the situation or past experiences with the stimulus. However, should a stimulus with a high affective valence e.g., a threatening object
come into play, the amygdala can over-ride the hippocampal influence, and instead direct behavior in a manner that can effectively deal with the
threatening stimulus. The motor plan that is selected by these interactions is then passed via the ventral pallidum to the mediodorsal thalamus where, via a
return loop to the prefrontal cortex, the selected motor plan can be enacted.
between amygdala activation and PFC stimulation, in that
the facilitation only occurred if the amygdala was activated
between 7 and 30 msec prior to PFC stimulation. There-
fore, as with the subiculum, the amygdala appears to be
capable of gating PFC throughput at the level of the
accumbens. However, in the case of the amygdala, this
gating appears to be more of a brief response that is likely
to be related more to event-related phenomena.
What are the functions of such gates? An evaluation of
the literature suggests that the hippocampal subiculum is
involved in modulating stimuli with respect to context.
Thus, several studies have implicated the subiculum in
context-dependent fear conditioning, and potentially other
types of context-related events 58 . Given the literature
suggesting that schizophrenics show deficits in tasks that
contain context-related information
consistent with a primary pathology in schizophrenia in-
volving the ventral hippocampus and its ability to gate
context-dependent information at the level of the accum-
bens 51 . In contrast, the amygdala has been associated
with stimuli related to emotion or affective state 35,70 .
Given the brief duration of the facilitation produced by
24,31,114 , this is
amygdala stimulation, the amygdala is proposed to gate
information based on its affective valence. Therefore, un-
der normal conditions, a person may be focused on a task
based on its context, which is driven by hippocampal
facilitation of information flow in the accumbens only
when the information conforms to the present context.
However, should a threatening stimulus be presented, the
amygdala should be capable of producing an over-ride of
the context information at the level of the accumbens,
instead facilitating those prefrontally-directed responses
that are related to escape. This would enable the organism
to respond to the threatening stimulus even if it is not
congruent with the current context Fig. 2; 51 .
5. Potential role for DA in modulating synaptic interac-
tions in the nucleus accumbens — the tonicr r r r rphasic
model of DA system regulation
As reviewed above, evidence indicates that there are
sufficient levels of DA in the extracellular fluid to produce
a tonic inhibition of PFC afferent input to accumbens
A.A. GracerBrain Research ReÕiews 31 2000 330–341
neurons 86 as well as to facilitate D1 modulation of dye
coupling in the core of the accumbens 85 . In contrast,
stimulation of D1 receptors in the accumbens appears to
require higher levels of DA agonists 85,89,102 . Indeed,
this type of information formed the bases for the develop-
ment of a hypothesis of schizophrenia based on the pres-
ence of two types of DA release 46 . In this model, DA
transmission is proposed to occur by way of two pro-
cesses: a tonic level of DA that is maintained at low i.e.,
20–50 nM; 26,111 concentrations in the extracellular
fluid ECF by potent homeostatic regulatory mechanisms,
and a phasic DA release into the synaptic cleft that is brief
in duration, yet achieves substantially higher concentra-
tions i.e., hundreds of mM up to mM levels;
Although the tonic DA levels in the ECF are probably too
low to act in a similar manner as DA released by spikes
intrasynaptically, this concentration is nonetheless ade-
quate to stimulate highly sensitive presynaptic receptors in
this region. These include the presynaptic D2 receptors
located on the corticoaccumbens terminals as well as the
DA autoreceptors located presynaptically on DA terminals,
which are reported to have an estimated Kd of 52 nM
102 . Indeed, a central tenet of this hypothesis is that tonic
DA levels mediate an inhibition of spike-dependent DA
release 46,48 . In this model, it is proposed that a behav-
iorally significant event will trigger DA cell burst firing
36,104 , which then drives the rapid, high-amplitude pha-
sic DA release into the synaptic cleft. In contrast, the low
level tonic DA present in the ECF is proposed to be
regulated by glutamatergic afferents 43,46 , such as those
coming from the PFC, amygdala, and the hippocampus
12,38 . In this model, I proposed that a pathological
disruption in one of the glutamatergic afferent systems that
innervate the accumbens e.g., from the hippocampus,
amygdala, or PFC causes a decrease in tonic DA levels.
As a result, there would be a potent disinhibition of phasic
DA release. In this way, the hyper-responsivity in the DA
system, e.g. 16,17,65,66 may be a consequence of a
failure of corticoaccumbens glutamate systems to provide
a tonic dopaminergic down-modulation of phasic DA sys-
tem function, causing the system to respond inappropri-
ately to otherwise insignificant stimuli. Although the
evidence for presynaptic glutamatergic regulation of DA
release is controversial 80 , recent studies 121 suggest
that DA release can occur via metabotropic glutamate
receptors. In synthesis, a pathological interruption of gluta-
matergic input from afferent cortical systems e.g., PFC,
hippocampus, amygdala could be responsible for the in-
crease in DA system responsivity in schizophrenia.
6. Synaptic plasticity and the impact of neonatal hip-
pocampal lesions on limbic system function in the adult
The evidence reviewed thus far indicates that lesions of
the ventral hippocampus in neonatal but not adult rats
leads to changes in DA regulation of limbic system-media-
ted behaviors in adult animals. However, the nature of this
alteration has not been investigated at the cellular level.
Therefore, we used another type of developmental disrup-
tion to mimic the pathophysiology of schizophrenia. As
described above, studies by Lipska and Weinberger
75,124 demonstrated the importance of developmental
disruption of the subiculum in altering the responsivity of
the limbic system. We used an approach that utilized a
mitotoxin, methyl azoxymethanol acetate MAM that ar-
rests cells in the process of division 23 . By adjusting the
timing of the administration and the dose of MAM, we
were able to administer doses of this drug that produced
cytoarchitectural changes in the hippocampus, entorhinal
cortex, and prefrontal cortex that were in many ways
analogous to what has been observed in schizophrenia.
Thus, administration of MAM to pregnant rats on gesta-
tional day GD 15–17 caused a dose-dependent disruption
in the development of the ventral hippocampal regions and
the surrounding perirhinal cortex when the brain was
examined after the rat reached adulthood 82 . These ani-
mals exhibited an increase in baseline locomotor activity
when placed in novel environments, and an enhancement
in the locomotor effects of PCP. In particular, there was an
enhancement of PCP-induced dyskinesias 41 . Although
such behaviors had previously been found with frontal
cortical damage in rats, the lack of substantial pathological
alterations in the frontal cortex suggests that this was a
developmental alteration in frontal cortical function that
resulted in such deficits. Indeed, MAM-treated rats also
exhibited an attenuation of DA-mediated inhibition of
pyramidal cell activity in the PFC in vivo 68 .
This enhanced response to PCP is interesting in light of
the observation that this drug will produce an extended and
symptom-specific enhancement of schizophrenia symp-
toms when administered to schizophrenia patients 76 .
This may be related to the fact that this compound is a
‘trapped’ NMDA receptor channel blocker 55 , which
requires membrane depolarization and NMDA channel
opening in order to eject the compound. Therefore, one
would expect PCP to exert particularly potent and long-
duration action at those glutamatergic synapses that re-
ceive a pathologically low level of glutamate stimulation
51,92,93 . This may provide an explanation both for the
potent actions in the schizophrenia patient as well as the
observation of a long-duration action in the MAM-treated
In addition to the effects on behavior, the MAM-treated
rats also exhibited an alteration in the interaction of limbic
afferents in the nucleus accumbens. Thus, whereas in
control rats amygdala stimulation was found to enhance
PFC-evoked spike discharge in the accumbens, in the
MAM-treated rat this interaction was significantly altered:
instead of facilitating throughput, amygdala stimulation
was found to attenuate PFC-evoked spike discharge. In-
deed, in the MAM-treated rats amygdala stimulation was
found to directly evoke accumbens cell spike discharge
A.A. GracerBrain Research ReÕiews 31 2000 330–341
rats. One hypothesis that could be drawn is that, if the
MAM model does indeed resemble the schizophrenic brain,
it suggests that schizophrenia patients may respond to
stimuli not on the basis of past experience or context
hippocampus driving a motor plan PFC , but instead
respond to all stimuli based on their affective valence Fig.
3; 51 . Such a condition may account for the reported
flooding of emotions and the inability to discriminate
relevant and irrelevant stimuli that are reported to be
present in the schizophrenia patient.
The reliance of these phenomena on developmental
disruptions may relate to the type of alteration that such
lesions may produce. Thus, one potential explanation that
may account for these findings is that the homeostatic
compensations produced neonatally in response to hip-
pocampal damage are not an attempt to restore functions
mediated by the ventral hippocampus directly, but instead
are directed toward compensating for the loss of its regula-
tory influence over other systems. A region in which all of
these aforementioned systems overlap is the nucleus ac-
cumbens. Within the accumbens, we have provided evi-
dence that the ventral hippocampus potently modulates
82 ; a response that was rarely observed in the control
PFC excitation of accumbens neurons, and thereby gates
PFC information throughput within this structure. Given
this condition, one could imagine that damage to this
hippocampal gating mechanism would result in an alter-
ation in the other ‘arm’ of this intersection to compensate
for this loss of regulation. This is proposed to involve
changes in the relationship between the corticoaccumbens
glutamatergic input and its modulation by DA. As cited
earlier, there is substantial evidence that glutamatergic
systems exert potent regulatory control over the induction
of long-term compensatory changes in the DA system
34,61 . Therefore, in this model, neonatal damage to the
hippocampus results in a reorganization within the corti-
coaccumbens system and its regulation by DA in order to
compensate for this loss of gating. One potentially interest-
ing result would be the attenuation of PFC efferent activity
following neonatal hippocampal lesions as a compensation
for inadequate gating control over these inputs. Such a
consequence could account for both the hypofrontalityrde-
creased PFC activation observed in this disorder 2,9,10,56
as well as provide an explanation for the apparent hyper-
responsivity of the DA system based on our tonic-phasic
model of DA system regulation 46 .
Fig. 3. The model presented in Fig. 2 is altered based on our results using the MAM model to approximate what is proposed to occur in the brain of the
schizophrenia patient. In this pathological state, the amygdala not only fails to facilitate prefrontal cortical throughput, but in this condition actually
competes with it for driving accumbens cell activity. Therefore, instead of selecting response strategies based on the goal-directed motor plan prefrontal
cortex as modulated by the current contextual constraints hippocampus , the system is biased to react exclusively based on the affective valence of the
stimulus. As a result, the planned behavior is replaced by impulsive responses based solely on the emotional state of the subject.
A.A. GracerBrain Research ReÕiews 31 2000 330–341
I would like to thank Dr. Holly Moore and Dr. Tony
West for preparing figures for this manuscript, and for
their helpful suggestions. This work was supported by
USPHS MH01055, MH57440, and MH45156. Dr. Grace is
a Wodecroft FellowrNARSAD Distinguished Investigator.
w x 1 M. Adler, Changes in sensitivity to amphetamine in rats with
chronic brain lesions, J. Pharmacol. Exp. Ther. 134 1961 214–224.
w x 2 N.C. Andreasen, K. Rezai, R. Alliger, V.W. Swayze 2nd, M.
Flaum, P. Kirchner, G. Cohen, D.S. O’Leary, Hypofrontality in
neuroleptic-naive patients and in patients with chronic schizophre-
nia. Assessment with xenon 133 single-photon emission computed
tomography and the Tower of London, Arch. Gen. Psychiatry 49
Ž . Ž.
12 1992 943–958.
w x 3 B. Angrist, J. Rotrosen, S. Gershon, Differential effects of am-
phetamine and neuroleptics on negative vs. positive symptoms in
schizophrenia, Psychopharmacology 72 1980 17–19.
w x 4 B. Angrist, G. Santhananthan, S. Wilk, S. Gershon, Amphetamine
psychosis: behavioral and biochemical aspects, J. Psychiatr. Res.
11 1974 13–23.
w x 5 B. Angrist, B. Shopin, S. Gershon, Comparative psychotomimetic
effects of stereoisomers of amphetamine, Nature 234 1971 152–
w x 6 S.E. Arnold, B.T. Hyman, G.W. Van Hoesen, A.R. Damasio, Some
schizophrenia, Arch. Gen. Psychiatry 48 1991 625–632.
w x 7 R.M. Beckstead, An autoradiographic examination of corticostriatal
and subcortical projections of the mediodorsal-projection prefron-
tal cortex in the rat, J. Comp. Neurol. 184 1979 43–62.
w x 8 R.M. Beckstead, V.B. Domesick, W.J. Nauta, Efferent connections
of the substantia nigra and ventral tegmental area in the rat, Brain
Res. 175 1979 191–217.
w x 9 K.F. Berman, R.F. Zec, D.R. Weinberger, Physiologic dysfunction
of dorsolateral prefrontal cortex in schizophrenia. II. Role of
neuroleptic treatment, attention, and mental effort, Arch. Gen.
Psychiatry 43 1986 126–135.
10 A. Bertolino, M.B. Knable, R.C. Saunders, J.H. Callicott, B.
Kolachana, V.S. Mattay, J. Bachevalier, J.A. Frank, M. Egan, D.R.
Weinberger, The relationship between dorsolateral prefrontal acety-
laspartate measures and striatal dopamine activity in schizophrenia,
Biol. Psychiatry 45 1999 660–667.
11 M. Beuger, D.P. van Kammen, M.E. Kelley, J. Yao, Dopamine
turnover in schizophrenia before and after haloperidol withdrawal
CSF, plasma, and urine studies, Neuropsychopharmacology 15
12 C.D. Blaha, C.R. Yang, S.B. Floresco, A.M. Barr, A.G. Phillips,
Stimulation of the ventral subiculum of the hippocampus evokes
glutamatereceptor-mediated changes in dopamine efflux in the rat
nucleus accumbens, Eur. J. Neurosci. 9 5
13 P.H. Boeijinga, C.M.A. Pennartz, F.H. Lopes da Silva, Paired-pulse
facilitation in the nucleus accumbens following stimulation of
subicular inputs in the rat, Neuroscience 35 1990 301–311.
14 P.H. Boeijinga, A.B. Mulder, C.M.A. Pennartz, I. Manshanden,
F.H. Lopes da Silva, Responses of the nucleus accumbens follow-
ing fornixrfimbria stimulation in the rat. Identification and long-
term potentiation of mono- and polysynaptic pathways, Neuro-
science 53 1993 1049–1058.
15 B. Bogerts, E. Meertz, R. Schonfeldt-Bausch, Basal ganglia and
Ž . Ž.
limbic system pathology in schizophrenia, Arch. Gen. Psychiatry
42 1985 784–791.
16 A. Breier, C.M. Adler, N. Weisenfeld et al., Effects of NMDA
antagonism on striatal dopamine release in healthy subjects: appli-
cation of a novel PET approach, Synapse 29 1998 142–147.
17 A. Breier, T.P. Su, R. Saunders et al., Schizophrenia is associated
with elevated amphetamine-induced synaptic dopamine concentra-
tions: evidence from a novel positron emission tomography method,
Proc. Natl. Acad. Sci. USA 94 1997 2569–2574.
18 J.P. Bruno, A.M. Snyder, E.M. Stricker, Effect of dopamine-deplet-
ing brain lesions on suckling and weaning in rats, Behav. Neurosci.
98 1984 156–161.
19 B.S. Bunney, A.A. Grace, Acute and chronic haloperidol treatment:
Comparison of effects on nigral dopaminergic cell activity, Life
Sci. 23 1978 1715–1728.
20 M.S. Buchsbaum, J. Cappelletti, R. Ball, E. Hazlett, A.C. King, J.
Johnson, J. Wu, L.E. DeLisi, Positron emission tomographic image
measurement in schizophrenia and affective disorders, Annals Neu-
Ž . Ž.
rol. 15 Suppl. 1984 S157–165.
21 M. Carlsson, A. Carlsson, Interactions between glutamatergic and
monoaminergic systems within the basal ganglia — implications
for schizophrenia and Parkinson’s disease, Trends Neurosci. 13
22 A. Carlsson, M. Lindqvist, Effect of chlorpromazine or haloperidol
on formation of 3-methoxytyramine and normetanephrine in mouse
brain, Acta Pharmacol. Toxicol. 20 1963 140–144.
23 F. Cattabeni, M. Di Luca, Developmental models of brain dysfunc-
tions induced by targeted cellular ablations with methyla-
zoxymethanol, Physiol. Rev. 77 1997 199–215.
24 L.J. Chapman, J.P. Chapman, G.A. Miller, A theory on verbal
behavior in schizophrenia, in: B. Maher Ed. , Prog. Experimental
Personality Research, Vol. I., Academic Press, New York, 1964,
25 M.J. Christie, R.J. Summers, J.A. Stephenson, D.J. Cook, P.M.
Beart, Excitatory amino acid projections to the nucleus accumbens
septi in the rat: a retrograde transport study utilizing D 3H aspartate
and 3H GABA, Neuroscience 22 1987 425–439.
26 W.H. Church, J.B. Justice, D.B. Neill, Detecting behaviorally
relevant changes in extracellular dopamine with microdialysis,
Brain Res. 412 1987 397–399.
27 A.J. Conrad, T. Abebe, R. Austin, S. Forsythe, A.B. Scheibel,
Hippocampal pyramidal cell disarray in schizophrenia as a bilateral
phenomenon, Arch. Gen. Psychiatry 48 1991 413–417.
28 J. Cornwall, O.T. Phillipson, Afferent projections to the dorsal
thalamus of the rat as shown by retrograde lectin transport. II. The
midline nuclei , Brain Res. Bull. 21 1998 147–161.
29 I. Creese, D.R. Burt, S.H. Snyder, Dopamine receptor binding
chizophrenic drugs, Science 192 1976 596–598.
30 J.F. DeFrance, R.W. Sikes, R.B. Chronister, Dopamine action in
the nucleus accumbens, J. Neurophysiol. 54 1985 1568–1577.
31 W.P. de Silva, D.R. Hemsley, The influence of context on language
perception in schizophrenia, Brit. J. Soc. Clin. Psychol. 16 1977
32 A.Y. Deutch, M.C. Lee, M.J. Iadarola, Regionally specific effects
of atypical antipsychotic drugs on striatal fos expression: the
nucleus accumbens shell as a locus of antipsychotic action, Molec.
Cell. Neurosci. 3 1992 332–341.
33 O. Devinsky, D. Luciano, The contribution of the cingulate cortex
to human behavior, in: B.A. Vogt, M. Gabriel Eds. , Neurobiology
of Cingulate Cortex and Limbic Thalamus: A Comprehensive
Handbook, Birkauser, Boston, 1993.
34 A. Emmi, H. Rajabi, J. Stewart, Behavioral and neurochemical
recovery from partial 6-hydroxydopamine lesions of the substantia
nigra is blocked by daily treatment with glutamate receptor antago-
nists MK-801 and CPP, J. Neurosci. 16 1996 5216–5224.
35 B.J. Everitt, M. Cador, T.W. Robbins, Interactions between the
A.A. GracerBrain Research ReÕiews 31 2000 330–341
amygdala and ventral striatum in stimulus-reward associations:
studies using a second-order schedule of sexual reinforcement,
Neuroscience 30 1989 63–75.
36 M. Fabre, E.T. Rolls, J.P. Ashton, G. Williams, Activity of neurons
in the ventral tegmental region of the behaving monkey, Behav.
Brain Res. 9 1983 213–235.
37 E.T. Fey, The performance of young schizophrenics and young
normals on the Wisconsin Card Sorting Test, J. Consulting Psy-
chol. 15 1951 311–319.
38 S.B. Floresco, C.R. Yang, A.G. Phillips, C.D. Blaha, Basolateral
amygdala stimulation evokes glutamate receptor-dependent dopa-
mine efflux in the nucleus accumbens of the anaesthetized rat, Eur.
Ž . Ž.
J. Neurosci. 10 41998 1241–1251.
39 K.J. Friston, The dorsolateral prefrontal cortex, schizophrenia and
PET, J. Neural Trans. 37 1992 79–93.
40 T.A. Fuller, F.T. Russchen, J.L. Price, Sources of presumptive
glutamergicraspartergic afferents to the rat ventral striatopallidal
region, J. Comp. Neurol. 258 1987 317–338.
41 M. Ghajarnia, H. Moore, A.A. Grace, Enhanced behavioral effects
of phencyclidine PCP in rats with developmental abnormalities of
the temporal lobe, Soc. Neurosci. Abstr. 24 1998 2177.
42 P.A. Garris, R.M. Wightman, Different kinetics govern dopaminer-
gic transmission in the amygdala, prefrontal cortex, and striatum:
an in vivo voltammetric study, J. Neurosci. 14 1994 442–450.
43 J. Glowinski, A. Cheramy, R. Romo, L. Barbeito, Presynaptic
regulation of dopaminergic transmission in the striatum, Cell.
Molec. Neurobiol. 8 1998 7–17.
44 T.E. Goldberg, D.R. Weinberger, K.F. Berman, N.H. Pliskin, M.H.
Podd, Further evidence for dementia of the prefrontal type in
schizophrenia? A controlled study of teaching the Wisconsin Card
Sorting Test, Arch. Gen. Psychiatry 44 1987 1008–1014.
45 P.S. Goldman-Rakic, The prefrontal contribution to working mem-
ory and conscious experience, in: O. Creuzfeld, J. Eccles Eds. ,
The Brain and Conscious Experience, Pontifical Academy Press,
46 A.A. Grace, Phasic versus tonic dopamine release and the modula-
tion of dopamine system responsivity: A hypothesis for the etiol-
ogy of schizophrenia, Neuroscience 41 1991 1–24.
47 A.A. Grace, The depolarization block hypothesis of neuroleptic
action: Implications for the etiology and treatment of schizophre-
nia, J. Neural Transm. 36 suppl.
48 A.A. Grace, Cortical regulation of subcortical dopamine systems
and its possible relevance to schizophrenia, J. Neural Transm. 91
49 A.A. Grace, B.S. Bunney, Induction of depolarization block in
nigral dopamine neurons by repeated administration of haloperidol:
Analysis using in vivo intracellular recording, J. Pharmacol. Exp.
Therapeut. 238 1986 1092–1100.
50 A.A. Grace, B.S. Bunney, H. Moore, C.L. Todd, Dopamine cell
depolarization block as a model for the therapeutic actions of
antipsychotic drugs, Trends Neurosci. 20 1997 31–37.
51 A.A. Grace, H. Moore, Regulation of information flow in the
nucleus accumbens:A model
schizophrenia, in: M.F. Lenzenweger, R.H. Dworkin Eds. , Ori-
gins and Development of Schizophrenia: Advances in Experimental
Washington, DC, 1998, pp. 123–157.
52 H.J. Groenewegen, Organization of the afferent connections of the
mediodorsal-prefrontal topography, Neuroscience 24 1998 379–
53 R.C. Gur, R.E. Gur, Hypofrontality in schizophrenia: RIP, Lancet
Ž . Ž.
345 8962 1995 1383–1384.
54 L. Heimer, D.S. Zahm, L. Churchill, P.W. Kalivas, C. Wohltmann,
Specificity in the projection patterns of accumbal core and shell in
the rat, Neuroscience 41 1991 89–125.
55 C.R. Honey, Z. Miljovic, J.F. MacDonald, Ketamine and phen-
cyclidine cause a voltage-dependent block of responses to L-aspartic
acid, Neurosci. Lett. 61 1985 135–139.
56 D.H. Ingvar, G. Franzen, Abnormalities of cerebral blood flow
distribution in patients with chronic schizophrenia, Acta. Psychiatr.
Scand. 50 1974 425–462.
57 S.D. Iversen, The effect of surgical lesions to frontal cortex and
substantia nigra on amphetamine responses in rats, Brain Res. 31
58 L.E. Jarrard, What does the hippocampus really do?, Behav. Brain
Res. 71 1995 1–10.
59 R.B. Jenkins, R.H. Groh, Mental symptoms in parkinsonian pa-
tients treated with L-DOPA, Lancet 2 7665
60 E.C. Johnstone, T.J. Crow, C.D. Frith, M.W.P. Carney, J.S. Price,
Mechanism of the antipsychotic effect in the treatment of acute
schizophrenia, Lancet 1 8069
61 P.W. Kalivas, Interactions between dopamine and excitatory amino
acids in behavioral sensitization to psychostimulants, Drug Alcohol
Depend. 37 1995 95–100.
62 A.E. Kelley, V.B. Domesick, The distribution of the projection
from the hippocampal formation to the nucleus accumbens in the
rat: an anterograde- and retrograde-horseradish peroxidase study,
Neuroscience 7 1982 2321–2335.
63 B. Kirkpatrick, R.W. Buchanan, The neural basis of the deficit
syndrome of schizophrenia, J. Nerv. Mental Disease 178 1990
64 J.A. Kovelman, A.B. Scheibel, A neurohistological correlate of
schizophrenia, Biol. Psychiatry 19 1984 1601–1917.
65 M. Laruelle, C.D. D’Souza, R.M. Baldwin et al., Imaging D2
receptor occupancy by endogenous dopamine in humans, Neu-
ropsychopharmacology 17 1997 162–174.
66 M. Laruelle, R.N. Iyer, M.S. al-Tikriti et al., Microdialysis and
SPECT measurements of amphetamine-induced dopamine release
in nonhuman primates, Synapse 25 1997 1–14.
67 A. Lavin, A.A. Grace, The modulation of dorsal thalamic cell
activity by the ventral pallidum: Its role in the regulation of
thalamocortical activity by the basal ganglia, Synapse 18 1994
68 A. Lavin, A.A. Grace, Effects of afferent stimulation and DA
application on prefrontal cortical cells recorded intracellularly in
vivo: comparisons between intact rats and rats with pharmacologi-
cally-induced disruption of cortical development, Soc. Neurosci.
Abstr. 23 1997 2080.
69 A. Lavin, A.A. Grace, Dopamine modulates the responsivity of
mediodorsal thalamic cells recorded in vitro, J. of Neurosci. 18
70 J.E. Ledoux, J. Muller, Emotional memory and psychopathology,
Phil. Trans. Royal Soc. London — Series B: Biological Sciences
352 1997 1719–1726.
71 L.S. Leung, C.Y.C. Yim, Rhythmic delta-frequency activities in the
nucleus accumbens of anesthetized freely moving rats, Can. J.
Physiol. Pharmacol. 71 1993 311–320.
72 P.F. Liddle, K.J. Friston, C.D. Frith, R.S.J. Frachowiak, Cerebral
blood flow and mental processes in schizophrenia, J. Royal Soc.
Med. 85 1992 224–227.
73 P.F. Liddle, K.J. Friston, C.D. Frith, S.R. Hirsch, T. Jones, R.S.J.
Frachowiak, Patterns of cerebral blood flow in schizophrenia, Brit.
J. Psychiatry 160 1992 179–186.
74 B.K. Lipska, G.E. Jaskiw, D.R. Weinberger, Postpubertal emer-
gence of hyperresponsiveness to stress and to amphetamine after
neonatal hippocampal damage: A potential animal model of
schizophrenia, Neuropsychopharmacology 9 1993 67–75.
75 B.K. Lipska, N.R. Swerdlow, M.A. Geyer, G.E. Jaskiw, D.L.
Braff, D.R. Weinberger, Neonatal excitotoxic hippocampal damage
in rats causes post-pubertal changes in prepulse inhibition of startle
and its disruption by apomorphine, Psychopharmacology 122 1995
76 E.D. Luby, J.S. Gottlieb, B.D. Cohen, G. Rosenbaum, E.F. Domino,
Ž . Ž.
A.A. GracerBrain Research ReÕiews 31 2000 330–341
Model psychoses and schizophrenia, Am. J. Psychiatry 119 1962
77 A.J. McDonald, Topographical organization of amygdaloid projec-
tions to the caudatoputamen, nucleus accumbens, and related stri-
atal-like areas of the rat brain, Neuroscience 44 1991 15–33.
78 K.M. Merchant, D.M. Dorsa, Differential induction of neurotensin
and c-fos gene expression by typical versus atypical antipsychotics,
Proc. Natl. Acad. Sci. USA 90 8
79 G.J. Mogenson, C.R. Yang, C.Y. Yim, Influence of dopamine on
limbic inputs to the nucleus accumbens, Ann. N.Y. Acad. Sci. 537
80 B. Moghaddam, R.J. Gruen, Do endogenous excitatory amino acids
influence striatal dopamine release?, Brain Res. 544 1991 329–
81 H. Moore, A.A. Grace, Interactions between amygdala and pre-
frontal cortical afferents to the nucleus accumbens and their modu-
lation by dopamine receptor activation, Soc. Neurosci. Abstr. 22
82 H. Moore, A.A. Grace, Anatomical changes in limbic structures
produced by methylazoxymethanol acetate MAM during brain
development are associated with changes in physiological interac-
tions among afferents to the nucleus accumbens, Soc. Neurosci.
Abstr. 23 1997 2378.
83 H.A. Nasrallah, R.C. Fowler, L.L. Judd, Schizophrenia-like illness
following head injury, Psychosomatics 22 1981 359–361.
84 P. O’Donnell, A.A. Grace, Physiological and morphological prop-
erties of accumbens core and shell neurons recorded in vitro,
Synapse 13 1993 135–160.
85 P. O’Donnell, A.A. Grace, Dopaminergic modulation of dye cou-
pling between neurons in the core and shell regions of the nucleus
accumbens, J. Neurosci. 13 1993 3456–3471.
86 P. O’Donnell, A.A. Grace, Tonic D2-mediated attenuation of corti-
cal excitation in nucleus accumbens neurons recorded in vitro,
Brain Res. 634 1994 105–112.
87 P. O’Donnell, A.A. Grace, Synaptic interactions among excitatory
afferents to nucleus accumbens neurons: Hippocampal gating of
prefrontal cortical input, J. Neurosci. 15 1995 3622–3639.
88 P. O’Donnell, A.A. Grace, Differential effects of subchronic cloza-
pine and haloperidol on dye coupling between neurons in the rat
striatal complex, Neuroscience 66 1995 763–767.
89 P. O’Donnell, A.A. Grace, Dopaminergic reduction of excitability
in nucleus accumbens neurons recorded in vitro, Neuropsychophar-
macology 15 1996 87–97.
90 P. O’Donnell, A.A. Grace, Hippocampal gating of cortical through-
put in the nucleus accumbens: Modulation by dopamine, Biol.
Psychiatry 39 1996 632.
91 P. O’Donnell, A.A. Grace, Cortical modulation of striatal gap
junction permeability is mediated via nitric oxide, Neuroscience 76
92 P. O’Donnell, A.A. Grace, Dysfunctions in multiple interrelated
systems as the neurobiological bases of schizophrenic symptom
clusters, Schizophr. Bull. 24 1998 267–283.
93 P. O’Donnell, A.A. Grace, Phencyclidine interferes with the hip-
pocampal gating of nucleus accumbens neuronal activity in vivo,
Neuroscience 87 1998 823–830.
94 S.-P. Onn, A.A. Grace, Dye coupling between rat striatal neurons
recorded in vivo: Compartmental organization and modulation by
dopamine, J. Neurophysiol. 71 1994 1917–1934.
95 S.-P. Onn, A.A. Grace, Repeated treatment with haloperidol and
clozapine exerts differential effects on dye coupling between neu-
rons in subregions of striatum and nucleus accumbens, J. Neurosci.
15 1995 7024–7036.
96 S.-P. Onn, A.A. Grace, Withdrawal following repeated am-
phetamine treatment increases dye coupling between neurons and
activates output pathways in rat limbic corticalrstriatal regions,
Soc. Neurosci. Abstr. 21 1995 1905.
Ž . Ž.
97 S.-P. Onn, A.A. Grace, Amphetamine differentially modulates gap
junctional permeability in limbic- vs motor-related striatal subre-
gions: Its correspondence with membrane excitability, Soc. Neu-
rosci. Abstr. 23 1997 1280.
98 C.M.A. Pennartz, M.J. Dollerman-van der Weel, S.T. Kitai, F.H.
Lopes da Silva, Presynaptic dopamine D1 receptors attenuate exci-
tatory and inhibitory limbic inputs to the shell region of the rat
nucleus accumbens, J. Neurophysiol. 67 1992 1325–1334.
99 R.M. Post, E. Fink, W.T. Carpenter, F.K. Goodwin, Cerebrospinal
fluid amine metabolites in acute schizophrenia, Arch. Gen. Psychia-
try 32 1975 1063–1069.
100 M. Reivich, D. Kuhl, A. Wolf, J. Greenberg, M. Phelps, T. Ido, V.
Casella, J. Fowler, E. Hoffman, A. Alavi, P. Som, L. Sokoloff, The
18F fluorodeoxyglucose method for the measurement of local
cerebral glucose utilization in man, Circulation Res. 44 1979
101 G.P.Reynolds,The amygdala
schizophrenia, in: J.P. Aggleton Ed. , The Amygdala: Neurobio-
logical Aspects of Emotion, Memory and Mental Dysfunction,
Wiley-Liss, New York, 1992.
102 E.K. Richfield, J.B. Penney, A.B. Young, Anatomical and affinity
state comparisons between dopamine D1 and D2 receptors in the
rat central nervous system, Neuroscience 30 1989 767–777.
103 G.S. Robertson, H.C. Fibiger, Neuroleptics increase c-fos expres-
sion in the forebrain: contrasting effects of haloperidol and clozap-
ine, Neuroscience 46 1992 315–328.
104 W. Schultz, R. Romo, Dopamine neurons of the monkey midbrain:
contingencies of responses to stimuli eliciting immediate behav-
ioral reactions, J. Neurophysiol. 63 1990 607–624.
105 G. Sedvall, L. Farde, A. Persson, F.A. Wiesel, Imaging of neuro-
transmitter receptors in the living human brain, Arch. Gen. Psychia-
try 43 1986 995–1005.
106 P. Seeman, Dopamine receptors and the dopamine hypothesis of
schizophrenia, Synapse 1 1987 133–152.
107 M. Segal, F.E. Bloom, The action of norepinephrine in the rat
hippocampus. III.Hippocampal cellular responses to locus
coeruleus stimulation in the awake rat, Brain Res. 107 1976
108 S.R. Sesack, A.Y. Deutch, R.H. Roth, B.S. Bunney, Topographical
organization of the efferent projections of the medial prefrontal
cortex in the rat: an anterograde tract-tracing study with Phaseolus
vulgaris leucoagglutinin, J. Comp. Neurol. 290 1989 213–242.
109 S.R. Sesack, V.M. Pickel, In the rat medial nucleus accumbens,
hippocampal and catecholaminergic terminals converge on spiny
neurons and are in apposition to each other, Brain Res. 527 1990
110 R.M. Shapiro, Regional neuropathology in schizophrenia: Where
are we? Where are we going?, Schizophr. Res. 10 1993 187–239.
111 T. Sharp, T. Zetterstrom, U. Ungerstedt, An in vivo study of
dopamine release and metabolism in rat brain regions using intrac-
erebral dialysis, J. Neurochem. 47 1986 113–122.
112 T. Sharp, T. Zetterstrom, T. Ljungberg, U. Ungerstedt, A direct
comparison of amphetamine-induced behaviours and regional brain
dopamine release in the rat using intracerebral dialysis, Brain Res.
401 1987 322–330.
113 S.H. Snyder, Catecholamines in the brain as mediators of am-
phetamine psychosis, Arch. Gen. Psychiatry 27 1972 169–179.
114 M. Spitzer, The psychopathology, neuropsychology, and neurobiol-
ogy of associative and working memory in schizophrenia, Eur.
Arch. Psychiatry Clin. Neurosci. 243 1993 57–70.
115 R.L. Suddath, G.W. Christison, E.F. Torrey, M.F. Casanova, D.R.
Weinberger, Anatomical abnormalities in the brains of monozy-
gotic twins discordant for schizophrenia, N. Eng. J. Med. 322
116 C.A. Tamminga, G.K. Thaker, R. Buchanan, B. Kirkpatrick, L.D.
Alphs, T.N. Chase, W.T. Carpenter, Limbic system abnormalities
() Download full-text
A.A. GracerBrain Research ReÕiews 31 2000 330–341
identified in schizophrenia using positron emission tomography
with fluorodeoxyglucose and neocortical alterations with deficit
syndrome, Arch. Gen. Psychiatry 49 1992 522–530.
117 N. Uchimura, H. Higashi, S. Nishi, Hyperpolarizing and depolariz-
ing actions of dopamine via D-1 and D-2 receptors on nucleus
accumbens neurons, Brain Res. 375 1986 368–372.
118 H.B.M. Uylings, C.G. van Eden, Qualitative and quantitative com-
parison of the prefrontal cortex in rat and in primates, including
humans, Prog. Brain Res. 85 1990 31–62.
119 D.P. van Kammen, W. Bok van Kammen, L.S. Mann, T. Seppala,
M. Linnoila, Dopamine metabolism in the cerebrospinal fluid of
drug-free schizophrenic patients with and without cortical atrophy,
Arch. Gen. Psychiatry 43 1986 978–983.
120 J.M. Van Rossum, The significance of dopamine-receptor blockade
for the actions of neuroleptic drugs, in: H. Brill, J.O. Cole, P.
Deniker, H. Hippius, P.B. Bradley, Eds. , Proc. of the 5th Col-
legium Internationale Neuropsychopharmacologicum, 1967, pp.
121 A. Verma, B. Moghaddam, Regulation of striatal dopamine release
by metabotropic glutamate receptors, Synapse 28 1998 220–226.
122 P. Voorn, B. Jorritsma-Byham, C. Van Dijk, R.M. Buijs, The
dopaminergic innervation of the ventral striatum in the rat: a light
and electron microscopical study with antibodies against dopamine,
J. Comp. Neurol. 251 1986 84–99.
123 D.R. Weinberger, Implications of normal brain development for the
pathogenesis of schizophrenia, Arch. Gen. Psychiatry 44 1987
124 D.R. Weinberger, B.K. Lipska, Cortical maldevelopment, anti-psy-
chotic drugs, and schizophrenia: a search for common ground,
Schizophr. Res. 16 1995 87–110.
125 M.E. Wolf, S.L. Dahlin, X.-T. Hu, C.-J. Xue, K. White, Effects of
lesions of prefrontal cortex, amygdala, or fornix on behavioral
sensitization to amphetamine: comparison with N-methyl-D-aspar-
tate antagonists, Neuroscience 69 1995 417–439.
126 C.Y. Yim, G.J. Mogenson, Mesolimbic dopamine projection modu-
lates amygdala-evoked EPSP in nucleus accumbens neurons: an in
vivo study, Brain Res. 369 1986 347–352.
127 C.Y. Yim, G.J. Mogenson, Neuromodulatory action of dopamine in
the nucleus accumbens: an in vivo intracellular study, Neuroscience
26 1988 403–415.
128 W.S. Young, G.F. Alheid, L. Heimer, The ventral pallidal projec-
tion to the mediodorsal thalamus: a study with fluorescent retro-
grade tracers and immunohistofluorescence, J. Neurosci. 4 1984