Review Paper

The role of the hippocampo-prefrontal cortex system in

phencyclidine-induced psychosis: A model for schizophrenia
Eiichi Jodo

Department of Neurophysiology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
a r t i c l e i n f o
Article history:
Available online 17 June 2013
Keywords:
PCP
Phencyclidine
MK801
NMDA
Prefrontal cortex
Hippocampus
Electrophysiology
Animal models
Schizophrenia
a b s t r a c t
Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy
individuals and exacerbates pre-existing symptoms in patients with schizophrenia. PCP also induces
behavioral and cognitive abnormalities in non-human animals, and PCP-treated animals are considered
a reliable pharmacological model of schizophrenia. However, the exact neural mechanisms by which
PCP modulates behavior are not known. During the last decade several studies have indicated that dis-
turbed activity of the prefrontal cortex (PFC) may be closely related to PCP-induced psychosis. Systemic
administration of PCP produces long-lasting activation of medial PFC (mPFC) neurons in rats, almost in
parallel with augmentation of locomotor activity and behavioral stereotypies. Later studies have showed
that such PCP-induced behavioral abnormalities are ameliorated by prior administration of drugs that
normalize or inhibit excess excitability of PFC neurons. Similar activation of mPFC neurons is not induced
by systemic injection of a typical psychostimulant such as methamphetamine, even though behavioral
hyperactivity is induced to almost the same level. This suggests that the neural circuits mediating
PCP-induced psychosis are different to those mediating methamphetamine-induced psychosis. Locally
applied PCP does not induce excitation of mPFC neurons, indicating that PCP-induced tonic excitation
of mPFC neurons is mediated by inputs from regions outside the mPFC. This hypothesis is strongly sup-
ported by experimental results showing that local perfusion of PCP in the ventral hippocampus, which
has dense ber projections to the mPFC, induces tonic activation of mPFC neurons with accompanying
augmentation of behavioral abnormalities. In this review we summarize current knowledge on the neural
mechanisms underlying PCP-induced psychosis and highlight a possible involvement of the PFC and the
hippocampus in PCP-induced psychosis.
2013 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
2. Pharmacology of PCP-induced psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
3. The role of the PFC in PCP-induced psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
4. Neural mechanisms mediating PCP-induced activation of PFC neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
5. PCP-treated animals as a model of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
6. Possibility of dysfunction in the hippocampo-prefrontal system in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
0928-4257/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jphysparis.2013.06.002
Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
GABA, c-aminobutylic acid; MD, mediodorsal nucleus of the thalamus; NMDA, N-
methyl-D-aspartate; PCP, phencyclidine; PFC, prefrontal cortex; mPFC, medial
prefrontal cortex.

Tel.: +81 24 547 1135; fax: +81 24 548 2571.

E-mail address: jodo1019@fmu.ac.jp
Journal of Physiology - Paris 107 (2013) 434440
Contents lists available at SciVerse ScienceDirect
Journal of Physiology - Paris
j our nal homepage: www. el sevi er . com/ l ocat e/ j physpar i s
1. Introduction
Phencyclidine (PCP) is a psychotomimetic drug that was origi-
nally developed as a general anesthetic (Sernyl

). PCP induces
schizophrenia-like symptoms in healthy humans (Domino and
Luby, 1981; Javitt and Zukin, 1991; Luby et al., 1959) and exacer-
bates existing symptoms in stabilized patients with schizophrenia
(Domino and Luby, 1981; Luby et al., 1959). Common symptoms of
schizophrenia are usually classied into two categories, positive
and negative symptoms. Positive symptoms include hallucination,
delusion, agitation, and hostility. Negative symptoms include
anhedonia, social withdrawal, blunted affect, and avolition. A typ-
ical psychostimulant such as methamphetamine generally induces
only positive symptoms and induces few negative symptoms, or
can even improve negative symptoms (Angrist et al., 1974; Thorn-
berg and Saklad, 1996). In contrast, PCP-induced psychosis in-
volves both positive and negative symptoms (Javitt and Zukin,
1991), as well as cognitive dysfunction (disturbed attention and
working memory) (Bakker and Amini, 1961). In non-human ani-
mals, systemic administration of PCP also produces cognitive and
behavioral abnormalities that correspond to the symptoms of
schizophrenia (Castellani and Adams, 1981; Haggerty et al.,
1984; Verma and Moghaddam, 1996). For example, PCP-treated
animals exhibited hyperlocomotion and stereotypic behaviors
(snifng, head swaying, rearing, etc.), which correspond to positive
symptoms of schizophrenia (Schlumberger et al., 2009), and de-
creased voluntary sucrose consumption (Turgeon and Hoge,
2003) and reduced social interaction with other animals
(Sams-Dodd, 1996; Lee et al., 2005), which correspond to negative
symptoms of schizophrenia. Furthermore, PCP-treated animals
exhibited poor performance in a delayed-response task (Adams
and Moghaddam, 1998), indicating disturbance in working mem-
ory; a typical cognitive decit in patients with schizophrenia.
PCP-treated animals provide a useful pharmacological model of
schizophrenia, and there is great interest in understanding the
neural mechanisms by which PCP modulates behavior. However,
the neural mechanisms involved in the development of PCP-in-
duced psychosis remain unclear. In this review we summarize cur-
rent knowledge on the neural mechanisms underlying PCP-
induced psychosis and highlight the possible involvement of the
prefrontal cortex (PFC) and the hippocampus in PCP-induced
psychosis.
2. Pharmacology of PCP-induced psychosis
PCP binds with high afnity to a site located in the ion channel
formed by the N-methyl-D-aspartate (NMDA)-type glutamate
receptor complex, and acts primarily as a non-competitive NMDA
receptor antagonist (Anis et al., 1983; Honey et al., 1985; Huettner
and Bean, 1988). At the high plasma concentrations that are asso-
ciated with anesthetic doses, PCP can also block many other types
of receptors, including norepinephrine, serotonin, and dopamine
receptors (Thornberg and Saklad, 1996). However, the psychotomi-
metic effects of PCP are observed at low concentrations, at which
PCP blocks only NMDA receptors (Thornberg and Saklad, 1996).
Systemically administered PCP increases dopamine efux in sev-
eral brain regions (Moghaddam and Adams, 1998), and it has pre-
viously been suggested that this increase in dopamine, rather than
antagonism of NMDA receptors, is the major factor underlying the
development of PCP-induced psychosis (Fessler et al., 1980;
Schlemmer et al., 1978). However, there are now many ndings
that contradict this hypothesis: NMDA receptor antagonist-in-
duced behavioral abnormalities were induced in monoamine-de-
pleted animals (Carlsson and Carlsson, 1989); PCP-induced
behavioral abnormalities were only blocked at doses of dopamine
antagonists that were high enough to induce catalepsy (Castellani
and Adams, 1981; Ogren and Goldstein, 1994); and dopamine
reuptake inhibitors that do not block NMDA receptors did not
reproduce the full range of PCP-induced behavioral abnormalities
(Koek et al., 1989). Therefore, it is now commonly accepted that
non-dopaminergic as well as dopaminergic mechanisms play a
key role in the development of PCP-induced psychosis.
Moghaddam and Adams (1998) demonstrated that normaliza-
tion of high glutamate release in the rat PFC ameliorated PCP-in-
duced behavioral abnormalities such as hyperlocomotion and
stereotypy without altering dopamine neurotransmission. Accord-
ingly, excessive efux of glutamate in the PFC is considered a pri-
mary factor responsible for the development of PCP-induced
psychosis.
3. The role of the PFC in PCP-induced psychosis
The PFC is one of the crucial regions implicated in schizophrenia
(Weinberger et al., 1986). A pivotal role of the PFC in the develop-
ment of PCP-induced psychosis is suggested by a clinical report
that patients who underwent prefrontal lobotomy were relatively
resistant to the psychotomimetic effects of PCP (Itil et al., 1967).
This suggests that PCP may induce psychosis by disturbing the
function of the PFC. Suzuki et al. (2002) demonstrated that sys-
temic administration of PCP produced long-lasting tonic excitation
of medial PFC (mPFC) neurons in freely moving rats, nearly in par-
allel with an increase in locomotor activity and stereotypy. Tonic
excitation of mPFC neurons was also induced by MK801, a more
selective NMDA receptor antagonist (Jackson et al., 2004). Similar
PCP- or MK801-induced activation of mPFC neurons was also ob-
served in anesthetized rats (Suzuki et al., 2002; Katayama et al.,
2007), indicating that PCP-induced activation of the mPFC was
not secondary to alteration of the arousal level due to increased
locomotor activity. Of course, we must take great care in compar-
ing data recorded in anesthetized animals with those in awake ani-
mals, because PCP can interact with anesthetic agents (Balster and
Wessinger, 1983). It is likely that some neural circuits that are ac-
tive in awake animals are not functional in anesthetized animals.
However, the neural circuits involved in PCP-induced tonic excita-
tion of mPFC neurons could be active even under anesthesia, if the
optimal depth of anesthesia is maintained (Suzuki et al., 2002;
Katayama et al., 2007).
Several studies have suggested a signicant link between
hyperlocomotion and tonic activation of the mPFC. As described
in Section 2, administration of a group II metabotropic glutamate
receptor agonist that suppressed PCP-induced excessive release
of glutamate in the mPFC blocked PCP-induced hyperlocomotion
(Moghaddam and Adams, 1998), suppressed MK801-induced tonic
excitation of mPFC neurons, and ameliorated hyperlocomotion
(Homayoun et al., 2005). Furthermore, clozapine, an atypical anti-
psychotic, also suppressed PCP-induced c-fos expression (a histo-
logical marker of neuronal excitation) in the mPFC (Kargieman
et al., 2007). Therefore, it is highly possible that improper activa-
tion of mPFC neurons is involved in the development of PCP-in-
duced behavioral abnormalities such as hyperlocomotion and
stereotypies, even though the mPFC itself does not directly produce
locomotor activity. In anesthetized animals, neural circuits that di-
rectly drive locomotor activity and receive ber projections from
the mPFC may be inactive or insensitive to excitatory inputs from
the mPFC.
A psychostimulant, methamphetamine, can also induce hyper-
locomotion and stereotypic behaviors to almost the same degree
as PCP. However, it has little effect on the spontaneous discharge
of mPFC neurons (Jodo et al., 2003). This indicates that the neural
circuits mediating PCP-induced psychosis are different to those
E. Jodo / Journal of Physiology - Paris 107 (2013) 434440 435
mediating methamphetamine-induced psychosis. As mentioned
above, PCP can induce both positive and negative schizophrenia-
like symptoms, whereasmethamphetamine induces primarily po-
sitive symptoms (Angrist et al., 1974; Thornberg and Saklad,
1996). Repeated administration of PCP can reliably induce social
withdrawal (Sams-Dodd, 1996) and avolition (Noda et al., 2000),
both of which are core negative symptoms of schizophrenia; there-
fore, repeated activation of the PFC over a long period of time may
be a key factor in triggering neural changes, such as a reduction of
dendritic spines and receptors, that are involved in the develop-
ment of negative symptoms in PCP-induced psychosis, and possi-
bly in schizophrenia. However, this is only speculation and needs
to be examined in future studies.
In studies on animal models of schizophrenia, the level of dis-
turbance in social interaction is often used as a measure of nega-
tive symptoms. Though many studies have demonstrated that
the amygdala plays a pivotal role in social behavior (Lee et al.,
2005; Sajdyk et al., 2008; Sajdyk and Shekhar, 1997; Truitt et al.,
2007), the PFC has also been implicated in social interaction (Car-
rier and Kabbaj, 2012; Elliott et al., 2012; Shah and Treit, 2003;
Wall et al., 2012). Jodo et al. (2010) demonstrated that about
one-third of mPFC neurons exhibited excitation during a social
interaction paradigm in which the rat was confronted with an
unfamiliar rat in the same chamber, and 80% of these neurons
exhibited tonic excitation to systemic administration of PCP. The
proportion of neurons activated by PCP was higher among neurons
that were excited by social interaction (80%) than among neurons
that were inhibited (40%) or unaffected (50%) by social interaction
(Jodo et al., 2010). This suggests that mPFC neurons that are ex-
cited by social interaction may be susceptible to activation by sys-
temic PCP.
4. Neural mechanisms mediating PCP-induced activation of PFC
neurons
To understand the neural mechanisms that mediate PCP-in-
duced activation of mPFC neurons it is rst necessary to establish
if activation of mPFC neurons is caused by direct action of PCP. In
several in vivo experiments (Gratton et al., 1987; Suzuki et al.,
2002; Jodo et al. 2005) PCP has been locally applied to mPFC neu-
rons while discharge activity of those neurons is recorded; how-
ever, no study has reported that locally applied PCP or MK801
excited mPFC neurons. In addition, the local application of PCP to
brain slices induced no detectable increase in excitatory postsyn-
aptic current in mPFC neurons (Aghajanian and Marek, 2000).
These ndings strongly suggest that direct pharmacological action
of PCP on mPFC neurons contributes little to PCP-induced activa-
tion of mPFC neurons. Rather, PCP-induced activation of mPFC neu-
rons may primarily be mediated via excitatory inputs from regions
outside the mPFC.
Though the mPFC receives excitatory inputs from many regions,
including the hippocampus (Jay and Witter, 1991), the mediodor-
sal nucleus of the thalamus (MD) (Groenewegen et al., 1990),
and the basolateral amygdala (Groenewegen et al., 1990), we have
focused on the hippocampus as a possible source of the excitatory
input involved in PCP-induced activation of mPFC neurons. We
consider the hippocampus to be a likely candidate because it, par-
ticularly the ventral part, has a dense glutamatergic projection to
the mPFC (Jay et al., 1992), disinhibitory activation of CA1 pyrami-
dal cells can be produced by PCP-induced inhibition of tonic c-ami-
nobutyric acid (GABA) inputs (Greene, 2001; Grunze et al., 1996),
and disturbances of hippocampal function and abnormalities in
hippocampal structure have been observed in patients with schizo-
phrenia (Hirayasu et al., 2000; Jessen et al., 2003). We demon-
strated that local perfusion of PCP in the ventral hippocampus of
rats produced tonic excitation of mPFC neurons without inducing
epileptiform electroencephalograph activity, almost in parallel
with the development of behavioral abnormalities such as hyperlo-
comotion and increased stereotypy (Jodo et al., 2005). This sug-
gests that PCP inuences the neuronal activity of the ventral
hippocampus, and that PCP-induced alteration of hippocampal
activity produces tonic excitation of mPFC neurons and behavioral
abnormalities.
To address the question of how NMDA-receptor antagonists like
PCP and MK801 affect the spontaneous discharge of ventral hippo-
campal neurons we examined the effects of locally applied MK801
on the spontaneous discharge of ventral hippocampal neurons
(CA1, subiculum). The direct projection of these neurons to the
mPFC was tested prior to drug application (Jodo et al., 2005). The
results showed that most (80%) hippocampal neurons with direct
projections to the mPFC exhibited excitation to locally applied
MK801, whereas only a few (<10%) hippocampal neurons without
direct projections to the mPFC did (Jodo et al., 2005). There were no
neurons in the mPFC that exhibited excitation to locally applied
MK801. These results suggest that hippocampal neurons with di-
rect projections to the mPFC are susceptible to activation by NMDA
receptor antagonists.
Greene (2001) proposed that PCP activates pyramidal neurons
in the hippocampus due to the relative paucity of NMDA receptors
on these cells. PCP blocks open channels in NMDA receptors (Dil-
more and Johnson, 1998; MacDonald et al., 1991). The number of
open (active) NMDA receptors is much larger on fast-spiking cells
such as GABAergic interneurons than on slow-spiking cells such as
pyramidal neurons; therefore, PCP acts faster and has a greater ef-
fect on these cells. This preferential blocking of NMDA receptors on
fast-spiking GABAergic interneurons produces disinhibition of
pyramidal neurons in the hippocampus and results in their activa-
tion. Indeed Greene (2001) reported results from in vitro studies
using hippocampal slices that support this hypothesis. However,
at present it is not known why hippocampal neurons that directly
project to the mPFC are particularly susceptible to PCP- or MK801-
induced excitation. Differences in receptor expression and local
circuits, including glial cells, between pyramidal cells and inter-
neurons may contribute to such preferential excitability, and this
should be examined in future studies.
The central tenet of our hypothesis is that PCP triggers neural
changes that are involved in the development of cognitive and
behavioral abnormalities by inducing tonic excitation of PFC neu-
rons, primarily via excitatory inputs from the hippocampus. How-
ever, several studies have reported experimental results that
appear to contradict this hypothesis. Kamiyama et al. (2011) dem-
onstrated that a subanesthetic dose of ketamine, an NMDA receptor
antagonist, decreased hippocampal stimulation-evoked potentials
in the mPFC of unanesthetized rats. This suggests that NMDAantag-
onists likely decrease hippocampus-mPFC excitatory synaptic
transmission, and therefore that excitatory inputs from the hippo-
campus contribute little to PCP-induced activation of PFC neurons.
They further showed that this suppression of hippocampal stimula-
tion-evoked potentials in the mPFC was mediated via augmented
GABA neurotransmission, though this seems contradictory to a pre-
vious nding that systemic PCP reduced extracellular concentration
of GABA in the mPFC (Yonezawa et al., 1998). A subanesthetic dose
of an NMDA receptor antagonist generally produces tonic excita-
tion of mPFC neurons (Suzuki et al., 2002; Jackson et al., 2004), sug-
gesting the existence of excitatory inputs that can overcome the
NMDA receptor antagonist-induced increases in GABAergic inhibi-
tion in the mPFC. Here, we need to differentiate between phasic and
tonic excitatory inputs. Tonic excitation of mPFC neurons induced
by NMDA receptor antagonists is likely mediated via tonic excit-
atory inputs to the mPFC. On the other hand, the hippocampal stim-
ulation-evoked eld responses of the mPFC recorded by Kamiyama
436 E. Jodo / Journal of Physiology - Paris 107 (2013) 434440
et al. were mediated via phasic excitatory inputs, because the hip-
pocampus-mPFC pathway was activated using brief electrical stim-
ulation. Tonic activation of mPFC neurons mediated via tonic
excitatory inputs from the hippocampus does not necessarily indi-
cate potentiation of phasic signal transmission in the hippocampus-
mPFC pathway. It is probable that a long-lasting increase in sponta-
neous discharge caused by tonic excitatory inputs degrades the sig-
nal-to-noise ratio forphasic excitatory inputs from the
hippocampus, and interferes with synchronized discharge activity
to the inputs in the mPFC. Therefore, the results of Kamiyama
et al. (2011) do not preclude NMDA receptor antagonist-induced to-
nic activation of the hippocampus-mPFC pathway.
In our hypothesis, the hippocampus is a primary source of
NMDA receptor antagonist-induced tonic excitatory inputs to the
mPFC, and these excitatory inputs play a pivotal role in the devel-
opment of behavioral abnormalities. If this hypothesis is correct,
animals with damage to the hippocampus, particularly to regions
with ber projections to the mPFC, should exhibit fewer behavioral
abnormalities after systemic administration of NMDA antagonists.
However Al-Amin et al. (2001) demonstrated that MK801-induced
hyperlocomotion was present even in rats with hippocampal le-
sions. There are two possible explanations to reconcile this contra-
dictory nding with our hypothesis. Firstly, it is possible that the
hippocampus-mPFC pathway is not the only route for inducing
behavioral abnormalities such as hyperlocomotion and stereotypy.
Though our previous study demonstrated that PCP-induced tonic
activation of the hippocampus-mPFC pathway was sufcient to in-
duce hyperlocomotion and stereotypy (Jodo et al., 2005), it did not
rule out the contribution of other regions and pathways to the
development of NMDA antagonist-induced behavioral abnormali-
ties. Another explanation is that in the study of Al-Amin et al.,
the hippocampal regions with ber projections to the mPFC may
have been preserved from lesion. Though they did not present de-
tails of lesioned area, they briey described it as follows: Neuro-
nal loss, cavitation, and gliosis was evident in all
cytoarchitectural subdivisions (CA1CA3) of the hippocampal for-
mation, as well as in portions of the dentate gyrus and subiculum
(Al-Amin et al., 2001, p. 531). This suggests that the subiculum,
which also has direct ber projections to the mPFC (Hoover and
Vertes, 2007), was partly intact. The hippocampal formation is a
relatively large structure in the brain, therefore it would be dif-
cult to lesion all regions with projections to the mPFC.
The receptors and transmitters that mediate PCP- and MK801-
induced tonic excitation of mPFC neurons are becoming better
understood. Systemic administration of PCP increases the extracel-
lular concentration of major transmitters including glutamate
(Moghaddam and Adams, 1998), acetylcholine (Jentsch et al.,
1998), norepinephrine (Li et al., 2010; Snell et al., 1988), serotonin
(Millan et al., 1999), and dopamine (Millan et al., 1999), but not
GABA (Yonezawa et al., 1998), in the mPFC. Of these transmitters,
glutamate and acetylcholine are possible candidates for mediating
PCP- and MK801-induced activation of mPFC neurons, because
they can directly excite mPFC neurons (Yang and Mogenson,
1990). Katayama et al. (2007) demonstrated that a locally applied
a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) /
kainate-type glutamate receptor antagonist suppressed PCP- and
MK801-induced excitation of mPFC neurons, whereas locally ap-
plied acetylcholine muscarinic- and nicotinic-receptor antagonists
had little effect. These results strongly indicate that PCP- and
MK801-induced activation of mPFC neurons is mediated by
AMPA/kainate-type glutamate receptors. Excitatory inputs from
the hippocampus to the mPFC are mostly mediated by AMPA/kai-
nate receptors (Jay et al., 1992); therefore, this is consistent with
our hypothesis that PCP- and MK801-induced activation of mPFC
neurons is produced mainly by excitatory inputs from the
hippocampus.
Fig. 1 shows a schematic representation of our hypothesis of the
neural mechanisms underlying PCP-induced psychosis. First, PCP
or MK801 preferentially excites hippocampal neurons with direct
projections to the mPFC. The mPFC neurons that receive inputs
from the hippocampus are then mildly or moderately excited via
AMPA/kainate-type glutamate receptors. Such mild and long-last-
ing activation of mPFC neurons without epileptiform activity trig-
gers neural changes that are involved in the development of
cognitive and behavioral abnormalities. Of course, we cannot rule
out the contribution of other pathways to PCP-induced psychosis.
Of other candidate pathways, the thalamo-prefrontal pathway
originating in the MD has attracted the most attention (Kargieman
et al., 2007; Konick and Friedman, 2001). Several studies have
demonstrated that systemic PCP can activate MD neurons. Kargi-
eman et al. (2007) showed that systemic administration of PCP in-
creased c-fos expression, a histological marker of neural excitation,
in the MD, and we previously showed that about one-third of MD
neurons exhibited tonic excitation to systemic PCP (Jodo et al.,
2010). These ndings indicate that the MD is a promising source
of PCP-induced excitatory inputs to the mPFC. However, some
studies have reported results that are contradictory to this hypoth-
esis. Electrical stimulation of the MD region inhibited excitation of
mPFC neurons by mbria/fornix stimulation in the majority of
mPFC neurons (Floresco and Grace, 2003), and stimulation of the
MD increased c-fos expression primarily in GABA-containing neu-
rons in the mPFC (Bubser et al., 1998). Further, in an ultrastructual
study, axons from the MD were found to primarily terminate not
on pyramidal neurons, but on GABAergic interneurons (Kuroda
et al., 1998). These ndings indicate that inputs from the MD
should have an inhibitory inuence on the discharge of pyramidal
neurons in the mPFC. Though little study has been performed on
the exact anatomical types of neurons that are activated or inhib-
ited by systemic PCP, Homayoun and Moghaddam (2007) demon-
strated that the majority of putative interneurons exhibited
suppression of spontaneous discharge to systemic PCP, whereas
the majority of putative pyramidal neurons exhibited activation,
suggesting that systemic PCP may activate pyramidal neurons in
the mPFC. Therefore, though we cannot rule out the involvement
of the thalamo-prefrontal pathway in the development of PCP-in-
duced psychosis, it seems not to be a major route, at least in the
development of PCP- and MK801-induced activation of mPFC
neurons.
It has been reported that systemic administration of PCP or
MK801 also produces tonic excitation of dopamine neurons in
AMPA/kainate
receptors
PCP
Hippocampus
E
E
Pyramidal
neuron
Behavioral abnormalities
PFC
Pyramidal
neuron
Disinhibition of
Inhibitory interneurons
?
Mild & tonic
activation
?
E
Thalamus ?
E ?
I ?
Behavioral abnormalities
?
Fig. 1. A schematic representation of our hypothesis on the neural mechanisms
underlying phencyclidine-induced psychosis. Solid arrows denote a direct inuence
or direct ber projection. Dotted arrows denote an indirect inuence or indirect
connection. The letters E and I indicate excitation and inhibition respectively.
The question mark (?) denotes a possible functional connection that has not yet
been conrmed. Abbreviations: PCP, phencyclidine; PFC, prefrontal cortex.
E. Jodo / Journal of Physiology - Paris 107 (2013) 434440 437
the ventral tegmental area (Ceci and French, 1989; Pawlowski
et al., 1990; Murase et al., 1993). The mPFC has reciprocal ber pro-
jections with the ventral tegmental area, which is a main source of
dopaminergic inputs to the mPFC (Umemoto et al., 1984). Many
studies have demonstrated that abnormal dopamine neurotrans-
mission plays a pivotal role in the development of cognitive and
behavioral abnormalities in various mental diseases including
schizophrenia (Carlsson, 1988), depression (Tye et al., 2013) and
drug abuse (Brown et al., 2012). Although the development of
PCP-induced behavioral abnormalities cannot be solely attributed
to abnormalities in the dopaminergic system as mentioned in the
previous section, systemic PCP increases the extracellular concen-
tration of dopamine in both the mPFC and the nucleus accumbens
(Moghaddam and Adams, 1998). Locally applied dopamine usually
inhibits the spontaneous discharge of mPFC neurons, mainly via D
2
receptors (Sesack and Bunney, 1989); therefore, the PCP-induced
increase in dopamine efux in the mPFC appears not to directly
contribute to PCP-induced mPFC activation. However, several stud-
ies have demonstrated that dopamine can indirectly modulate the
excitability of mPFC neurons via D
1
receptor-dependent GABA in-
puts (Kamiyama et al., 2011), and can modulate long-term poten-
tiation of mPFC responsiveness to hippocampal stimulation
(Gurden et al., 2000). Therefore, it is probable that a PCP-induced
sustained increase in dopamine efux in the mPFC or the nucleus
accumbens modulates synaptic transmission of other transmitters,
and may alter plasticity of neural connections, which may contrib-
ute to the pathogenesis of PCP-inducedpsychosis.
5. PCP-treated animals as a model of schizophrenia
Most of the antipsychotics that are effective for treating schizo-
phrenia have a pharmacological action as an antagonist of dopa-
mine receptors, particularly D
2
receptors, and the binding afnity
of antipsychotics to D
2
receptors is inversely related to their ther-
apeutic dose (Creese et al., 1976; Seeman et al., 1976). This indi-
cates that disturbance or hyperactivation of dopamine
neurotransmission contributes to symptom development in
schizophrenia. This dopamine hypothesis is the most inuential
theory on the pathogenesis of schizophrenia; however, there are
several ndings that challenge the dopamine hypothesis. Gener-
ally, at least several days are needed before remission of positive
symptoms is evident after initiation of antipsychotic medication
(Garver et al., 1984), whereas dopamine neurotransmission is al-
tered within several hours (Berwaerts et al., 2010). Some patients
exhibited little reduction in their positive symptoms, even when
over 90% of D
2
receptors were occupied by antipsychotics (Coppens
et al., 1991), and antipsychotics do little to ameliorate negative
symptoms and cognitive dysfunction (Tandon et al., 2008).
Although these facts challenge the dopamine hypothesis, they do
not preclude the involvement of the dopaminergic system in the
pathogenesis of schizophrenia. Dopamine may be indirectly
responsible for symptoms in schizophrenia, and non-dopaminergic
mechanisms may also contribute to development of symptoms in
schizophrenia. PCP can indirectly modulate dopamine transmis-
sion and may produce psychosis that is at least initially mediated
by a nondopaminergic mechanism, therefore PCP-treated animals
as a model of schizophrenia may reect nondopaminergic aspects
(i.e. the glutamate hypothesis) in the pathogenesis of
schizophrenia.
6. Possibility of dysfunction in the hippocampo-prefrontal
system in schizophrenia
In a postmortem neuropathological study of patients with
schizophrenia, the density of basilar dendritic spines on layer 3
pyramidal neurons in the dorsolateral PFC was signicantly de-
creased relative to that of control subjects (Glantz and Lewis,
2000). Dendritic spines are the principal site of excitatory inputs
to the pyramidal neurons (DeFelipe and Farinas, 1992), therefore
Glantz and Lewis (2000) suggested that decreased spine density
in patients with schizophrenia might result from excessive excit-
atory inputs to the PFC. Although they considered the thalamus
to be the possible source, such structural changes may also be
due to the down-regulation of excitatory synapses that is caused
by tonic excitatory inputs over a long period. Another clinical study
demonstrated that regional blood volume in the hippocampal CA1
area was larger in patients with schizophrenia than in non-patients
and, in a longitudinal study, hippocampal blood volume was larger
in individuals who went on to develop psychosis than in individu-
als who did not (Schobel et al., 2009). Regional blood volume re-
ects the local activity of neurons; therefore, this nding
indicates that individuals who developed psychosis had higher
neuronal activity in the hippocampal CA1 region even before the
development of symptoms. These human studies suggest that both
long-lasting abnormal excitatory inputs to the PFC and hyper-acti-
vation of the hippocampal CA1 region may be present in patients
with schizophrenia and individuals at high risk of developing
schizophrenia.
In this review we have presented the hypothesis that tonic acti-
vation of the PFC via the excitatory pathway from the hippocam-
pus is critical in the development of PCP-induced psychosis
(Fig. 1). Results from human studies further suggest that long-last-
ing activation of the PFC without epileptiform activity may also oc-
cur in the early stages of schizophrenia, even before the
development of symptoms. If the hypothesis that tonic activation
of the PFC plays a pivotal role in the development of schizophrenia
is conrmed and the neural mechanisms are fully elucidated, this
will provide a promising avenue for the development of new strat-
egies for the prevention and treatment of schizophrenia.
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