NIH Preclinical Models of Antipsychotic Drug Action

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Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.
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Published in final edited form as:

Int J Neuropsychopharmacol. 2013 November ; 16(10): 2131–2144. doi:10.1017/S1461145713000606.
Preclinical models of antipsychotic drug action

José L. Moreno1 and Javier González-Maeso1,2,3
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
2Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
3Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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Abstract
One of the main obstacles faced by translational neuroscience is the development of animal
models of psychiatric disorders. Behavioural pharmacology studies indicate that psychedelic
drugs, such as lysergic acid diethylamide (LSD) and dissociative drugs, such as phencyclidine
(PCP), induce in healthy human volunteers psychotic and cognitive symptoms that resemble some
of those observed in schizophrenia patients. Serotonin 5-HT2A and metabotropic glutamate 2
receptors have been involved in the mechanism of action of psychedelic and dissociative drugs.
Here we review recent advances using LSD-like and PCP-like drugs in rodent models that
implicate these receptors in the neurobiology of schizophrenia and its treatment.
Keywords
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Antipsychotic drugs; epigenetics; lysergic acid diethylamide; metabotropic glutamate 2 receptor;

mouse models; phencyclidine; schizophrenia; serotonin 5-HT2A receptor
Introduction
Schizophrenia is a chronic mental disorder that afflicts nearly 1% of the population
worldwide (Sawa and Snyder, 2002; Freedman, 2003; Tamminga and Holcomb, 2005; Lewis
and Gonzalez-Burgos, 2006; Ross et al., 2006; van Os and Kapur, 2009; Abbott, 2010;
Dobbs, 2010). The first symptoms of schizophrenia generally occur in late adolescence or
early adulthood and continue into adult life. These include positive symptoms, such as
hallucinations and delusions, and negative symptoms such as alogia (poverty of speech),
avolition (lack of motivation) and anhedonia (lack of pleasure). Cognitive deficits, including
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altered working memory and disordered thought, are present in the majority of
schizophrenia patients and are responsible for a significant portion of impairments and
disabilities associated with schizophrenic disorders (Green, 1996; Barch and Ceaser, 2012;
Minzenberg and Carter, 2012; Curley et al., 2013). It has also been shown that suicide is one
the principal causes of death in schizophrenia patients, with a 50% lifetime risk for suicide
Address for correspondence: Dr J. González-Maeso, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One
Gustave L. Levy Place, Box 1229, New York, NY 10029, USA. Tel.: 212 824 8973 Fax: 646 537 9583, Javier.Maeso@mssm.edu.
Statement of Interest
None.
Moreno and González-Maeso Page 2
attempts in patients with schizophrenia as compared with approximately 5% in the general

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population (Meltzer et al., 2003a; Hawton et al., 2005; Pompili et al., 2007; Saha et al.,
2007).
It is well established that genetics plays a significant role in schizophrenia and schizophrenia
spectrum disorders (International Schizophrenia Consortium, 2008; Stefansson et al., 2008,
2009; Walsh et al., 2008; Purcell et al., 2009; Vacic et al., 2011). However, the study of
family members supports the conclusion that genetic factors are not sufficient to cause
schizophrenia (Tsuang et al., 2001). As discussed earlier, the lifetime prevalence of
schizophrenia in the general population is about 1%. This risk of developing schizophrenia
increases with the degree of genetic relatedness to the patient. As an example, third-degree
relatives (e.g. first cousins) share about 12.5% of their genes and show a risk of developing
schizophrenia of approximately 2%. Second-degree relatives (e.g. half-siblings) share
approximately 25% of the genes and show a risk of 6%; whereas first-degree relatives (e.g.
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siblings and dizygotic twins) share approximately 50% of the genes and show a risk of about
9%. Monozygotic twins, whose DNA sequences are almost 100% identical, have a
concordance for schizophrenia of nearly 50% (McGuffin et al., 1994; Cardno and
Gottesman, 2000; Gottesman and Erlenmeyer-Kimling, 2001). Such results support the
conclusion that genetics plays a significant role in the aetiology of schizophrenia. At the
same time, they also favour a significant contribution of environmental factors in the
development of this complex disease (Lewis and Levitt, 2002; Bale et al., 2010).
Epidemiological studies have demonstrated that maternal adverse life-events during
pregnancy such as famine, war and death of a relative, increase the risk of schizophrenia in
the new-borns (Bradley and Dinan, 2010; Markham and Koenig, 2011). It has also been
shown that maternal infection during pregnancy raises the risk for schizophrenia in the
offspring (Yolken and Torrey, 2008; Brown and Derkits, 2010; Patterson, 2011). Of
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particular interest and one of the focuses of this review is the generation of animal models
that may help understand the molecular mechanisms through which maternal/foetal
gene×environment interactions contribute to the onset of schizophrenia and other psychiatric
disorders later in life.
The antipsychotic drugs currently available for clinical use are able to ameliorate some of
the symptoms in schizophrenia patients, rather than to reverse the underlying alterations
responsible for the disease. Because of this, schizophrenia is still defined as an incurable
psychiatric disorder and its treatment typically continues for life. It is reasonable to suspect
that schizophrenia, as currently defined, represents a unique human disorder and,
consequently, modelling its phenotypic expression in rodent models remains controversial
(Arguello and Gogos, 2006; Powell and Miyakawa, 2006; Powell and Geyer, 2007; Geyer,
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2008; Pratt et al., 2008; Kellendonk et al., 2009; O’Tuathaigh et al., 2009; Nestler and
Hyman, 2010; van den Buuse, 2010; Fernando and Robbins, 2011; Geyer et al., 2012). The
neurodevelopmental stages, as well as the anatomical location and neuronal circuits involved
in processes of cognition and perception, differ between humans and rodents, which also
raises concerns with respect to the translation of preclinical findings into clinical use.
Consequently, one of the limitations in molecular psychiatry in general and in schizophrenia
research in particular, is the development of rodent models that may help identify new
targets for antipsychotic drug development. In this review, we summarize recent advances in

our understanding, based on rodent models of psychedelic or dissociative drug exposure, of

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not only the complex mechanisms associated with antipsychotic drug action, but also the
origins of schizophrenia itself.
Pharmacological models of psychosis and antipsychotic drug action

Glutamatergic dissociative drugs such as phencyclidine (PCP), ketamine and dizolcipine
(MK801), behave as non-competitive N-methyl-D-aspartate receptor antagonists (Morris et
al., 2005; Kristiansen et al., 2007). In an innovative study, Krystal et al. (1994) demonstrated
that administration of sub-anaesthetic doses of ketamine into healthy volunteers induces
negative symptoms and alterations in working memory and cognition that resemble those
observed in schizophrenia patients. A single administration of ketamine does not recreate
positive symptoms such as hallucinations, although paranoia and thought disorder are
induced (Krystal et al., 1994). Follow-up studies testing the effects of dissociative drugs in
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healthy volunteers further validated these findings, suggesting alterations in time and
sensory perception, thought, speech, mood and affect that resemble some of the psychotic
states, negative symptoms and cognitive deficits associated with schizophrenia
(Vollenweider et al., 1997a, b, 2000; Adler et al., 1999; Newcomer et al., 1999; Umbricht et
al., 2000, 2002; Cho et al., 2005; Krystal et al., 2005; Schmidt et al., 2012, 2013; Driesen et
al., 2013). This is supported by the effects of chronic abuse of PCP, which commonly lead to
a misdiagnosis of schizophrenia (Rainey and Crowder, 1975; Allen and Young, 1978;
Pearlson, 1981; Cosgrove and Newell, 1991), whereas PCP administration to schizophrenia
patients who are not receiving antipsychotic treatment aggravates positive symptoms (Lahti
et al., 2001). Together, these findings point toward a potential dysregulation in glutamatergic
synaptic transmission as potentially involved in negative and cognitive symptoms of
schizophrenia, as well as in positive symptoms, and support the use of PCP-like dissociative
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drugs in animals as a preclinical model of psychosis-like behaviour.
Serotonin (5-HT), and in particular the 5-HT2A receptor, has received much attention with
regard to schizophrenia and psychosis (Geyer and Vollenweider, 2008; Aghajanian, 2009;
Gonzalez-Maeso and Sealfon, 2009b; Geyer et al., 2012). The hallucinogenic properties of
the semi-synthetic compound d-lysergic acid diethylamide (LSD) were discovered
serendipitously by Albert Hoffman in 1943 (Hofmann, 1959). The 5-HT hypothesis about
the mechanism of action of LSD was proposed based on the structural similarities between
5-HT and hallucinogenic drugs such as LSD and psilocin, and the identification of 5-HT as a
neurotransmitter (Dahlstrom and Fuxe, 1964). Later in the 1980s, Richard Glennon, Milt
Titeler and their collaborators showed a highly significant correlation between the affinities
of 22 hallucinogenic compounds for 5-HT2 binding sites and their hallucinogenic potency in
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humans (Glennon et al., 1984). This milestone work also demonstrated a significant
correlation between the 5-HT2 binding affinities of these agents and drug discrimination
ED50 values in rats (Glennon et al., 1984). Further work in healthy volunteers showed that
the psychoactive effects of psychedelic drugs such as LSD, mescaline, psilocybin, and N, N-
dimethyltryptamine drugs share several features with schizophrenia, including: perceptual
disturbances; sensory processing; cognition; changes in brain metabolism; self-
representation (Young, 1974; Hermle et al., 1992; Vollenweider et al., 1998; Gouzoulis-
Mayfrank et al., 2005; Quednow et al., 2011; Carhart-Harris et al., 2012). Indeed, LSD

effects were one of the earliest models of schizophrenia (Keeler, 1965) and are currently
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believed to model in normal subjects positive symptoms (e.g. hallucinations and delusions)
comparable to those seen in drug-naive first-episode schizophrenia patients (Geyer and
Vollenweider, 2008; Gonzalez-Maeso and Sealfon, 2009b; Geyer et al., 2012) through a
mechanism that involves activation of the 5-HT2A receptor in cortical glutamatergic neurons
(Beique et al., 2007; Gonzalez-Maeso et al., 2007; Celada et al., 2008). It has also been
suggested that relatives of schizophrenic patients are more susceptible to the psychotic
responses induced by LSD (Anastasopoulos and Photiades, 1962). Although LSD-like drugs
as a model of psychosis have limitations (Hays and Tilley, 1973), these findings suggest that
a better understanding of their molecular mechanism of action may provide additional
insights into the brain processes underlying non-drug-induced psychoses.
Given that schizophrenia is exclusively human, the generation of animal models remains
controversial. However, based on their effects in healthy volunteers, psychedelic and
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dissociative drugs have been considered effective as a tool to model distinct aspects of
schizophrenia in rodents and consequently disruption of their behavioural effects has been
used as a model that predicts antipsychotic responses in terms of positive, negative or
cognitive deficits, depending on the behavioural paradigm used, as well as on whether PCP-
like or LSD-like drugs are employed to model psychosis. Some of these behavioural models
include those following.
Modulation of locomotor activity

In rodents, PCP-like drugs induce hyperlocomotor activity and modulation of this
behavioural effect has been repeatedly used as a model of antipsychotic action. It has been
suggested that the 5-HT2A receptor is at least in part involved in the effects of atypical (e.g.
clozapine, risperidone and olanzapine), but not typical (e.g. haloperidol and
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chlorpromazine), antipsychotics on the hyperlocomotor response induced by dissociative

drugs (Gleason and Shannon, 1997; Bradford et al., 2010; Fribourg et al., 2011; Yadav et al.,
2011b). The authors demonstrated that the locomotor response induced by PCP-like drugs in
mice was reduced by haloperidol only at doses at which it also reduces the locomotor
response in the absence of PCP-like drugs. In contrast, the atypical antipsychotics clozapine
and olanzapine reduced the locomotor activity induced by PCP-like drugs at doses that were
significantly lower than those that alone affect exploratory behaviour. Atypical
antipsychotics all have in common a high affinity for the 5-HT2A receptor and a much lower
affinity for the dopamine D2 receptor (Miyamoto et al., 2005; Lieberman et al., 2008).
Typical antipsychotics, on the contrary, have an antagonistic effect at the dopamine D2
receptor that has been involved in their mechanism of action (Carlsson et al., 2001; Meltzer
et al., 2003b). Importantly, it has been demonstrated that selective 5-HT2A receptor
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antagonists such as volinanserin (M100907) reduce the locomotor hyperactivity induced by

PCP-like drugs in rats and that these doses by themselves do not affect exploratory
behaviour (Maurel-Remy et al., 1995). Similar data were obtained in mice (Carlsson, 1995).
The role of 5-HT2A receptors in the effects of clozapine on the locomotor response induced
by PCP-like drugs has been recently supported by the use of 5-HT2A knockout mice
(Fribourg et al., 2011). Although the pre-synaptic component of the serotonergic system
plays an important role in the antipsychotic-like properties of clozapine (Yadav et al.,

2011a), these results with knockout mice suggest that the 5-HT2A receptor is at least
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involved in the therapeutic-like effects of atypical antipsychotics, using hyperlocomotor

activity induced by PCP-like drugs as a rodent model of psychosis. Recent findings also
point toward a role of 5-HT2A receptors expressed in cortical glutamatergic neurons in the
effects of high doses of clozapine, but not haloperidol or risperidone, on locomotor
suppression (McOmish et al., 2012; Williams et al., 2012).
The psychedelic 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) has

been shown to affect locomotor activity in mice (Gonzalez-Maeso et al., 2007; Halberstadt
et al., 2009, 2013) and rats (Krebs-Thomson et al., 1998; Van Oekelen et al., 2003; Marona-
Lewicka et al., 2005). Low doses of DOI significantly increase locomotor activity, an effect
that is absent in 5-HT2A knockout mice (Halberstadt et al., 2009). However, locomotor
activity and exploratory behaviour is reduced in mice injected with higher doses of DOI, an
effect that remains unaffected in 5-HT2A knockout mice and is reversed by the selective 5-
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HT2C receptor antagonist SER-082 (Halberstadt et al., 2009). These results suggest that both
5-HT2A and 5-HT2C receptors are involved in the inverted U-shaped dose–response effect of
DOI on the locomotor response in mice. A more detailed characterization of the effects of
phenylalkylamine psychedelics, including low doses of DOI, mescaline, 2,5-dimethoxy-4-
ethylamphetamine, 2,5-dimethoxy-4-propylamphetamine, 2,4,5-trimethoxyamphetamine
and 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl-methylamine (TCB-2), shows increased
locomotor activity in wild-type mice, an effect that is blocked by M100907 and abolished in
5-HT2A knockout mice (Halberstadt et al., 2013). Interestingly, the effect on locomotor
hyperactivity induced by phenylalkylamine psychedelics is not induced by the non-
psychedelic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB; Halberstadt
et al., 2013). These findings suggest that activation of the 5-HT2A receptor by psychedelics,
but not by non-psychedelics, increases locomotor activity in mice, which may serve as a
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model of hallucinogenic potential in humans. Using pharmacological tools in rats, it has

been shown that the effects of the phenylalkylamine DOI on exploratory behaviour are
reversed by the 5-HT2A receptor antagonist M100907, whereas those of the ergoline LSD
are not (Krebs- Thomson et al., 1998). Together, these findings in mice and rats support the
link between activation of the 5-HT2A receptor and the unique behavioural effects of
phenylalkylamine psychedelics. However, further work is needed to define the
pharmacological and molecular mechanisms, such as activation of dopamine D2 receptors
(Marona-Lewicka et al., 2005) underlying the differential effects of phenylalkylamine and
ergoline psychedelics on locomotor activity and other rodent behaviours.
Head-twitch behaviour
Head-twitch behavioural response in rodents is a rapid lateral movement of the head similar
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to the pinna reflex (Canal and Morgan, 2012). It has been shown to be induced by a variety
of psychedelic 5-HT2A receptor agonists such as DOI, 1-(2,5-dimethoxy-4-methylphenyl)-2-
aminopropane, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), mescaline, LSD,
TCB-2 and psilocin (Gonzalez-Maeso et al., 2003, 2007; Benneyworth et al., 2008; Canal et
al., 2010; Fox et al., 2010; Halberstadt and Geyer, 2013) and reversed by 5-HT2A receptor
antagonists (Fantegrossi et al., 2005; Benneyworth et al., 2008; Fribourg et al., 2011). This
behaviour is different as compared to head-weaving (slow, side-to-side lateral head

movements induced by dissociative drugs; Kozlenkov and Gonzalez-Maeso, 2012) and wet-
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dog shake behaviour (repetitive shaking of the body commonly observed in rodents during
morphine withdrawal; Martin et al., 1963). Importantly, the head-twitch behaviour induced
by psychedelic drugs is absent in 5-HT2A knockout mice (Gonzalez-Maeso et al., 2003) and
rescued in mice that express 5-HT2A receptors only in cortical glutamatergic neurons
(Gonzalez-Maeso et al., 2007). Direct injection of psychedelic drugs into medial prefrontal
cortex provides additional evidence that head-twitch behaviour is mediated through cortical
5-HT2A receptors (Willins and Meltzer, 1997; see also Gresch et al., 2002 for data
suggesting a role of cortical 5-HT2A receptors in the discriminative stimulus properties of
LSD).
A long-lasting question in neuropharmacology has been the molecular mechanisms

underlying the unique behavioural responses induced by psychedelics as compared with
those induced by non-psychedelic 5-HT2A receptor agonists (Nichols, 2004; Gonzalez-
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Maeso and Sealfon, 2009a). Thus, non-psychedelic 5-HT2A receptor agonists such as
lisuride, ergotamine and DOTB, bind with high affinity to and activate the 5-HT2A receptor
with similar potencies and efficacies as those observed by psychedelic drugs (Egan et al.,
1998; Hoyer et al., 2002). It has been recently shown that only 5-HT2A receptor agonists
with psychedelic potential in humans induce a significant head-twitch behaviour in mice and
that this behavioural response is not induced by non-psychedelic drugs such as lisuride and
ergotamine (Gonzalez-Maeso et al., 2003, 2007). Similar results have recently been reported
with the use of a head-mounted magnet and a magnetometer coil (Halberstadt and Geyer,
2013). Together, these findings suggest that head-twitch behaviour may be used as a rodent
behavioural model of psychedelic potential in humans.
Modulation of psychedelic-dependent head-twitch behaviour has also been tested as a model

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of antipsychotic action (see later for discussion).
Prepulse inhibition of startle

The development of psychosis is the most striking element of schizophrenia, but deficits in
the sensory gating have now been shown as core features of the illness (Barch and Ceaser,
2012; Lewis et al., 2012; Minzenberg and Carter, 2012). Prepulse inhibition (PPI) is a
behavioural model that measures sensorimotor gating. In this model, a weak pre-stimulus
(auditory or tactile) reduces the startle response to a subsequent intense startling stimulus
(Geyer and Ellenbroek, 2003). Patients with schizophrenia exhibit deficits in PPI models of
the acoustic startle reflex (Ludewig et al., 2003) and impaired PPI response can be used as a
measure of alterations in sensorimotor gating in healthy volunteers (Heekeren et al., 2007).
PCP-like drugs produce PPI deficits in mice (Dulawa and Geyer, 1996), rats (Mansbach and
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Geyer, 1989, 1991) and non-human primates (Javitt and Lindsley, 2001; Linn and Javitt,
2001). It has also been demonstrated that the psychedelic drugs DOI and LSD disrupt PPI,
an effect that is reversed by selective 5-HT2A antagonists such as M100907 (Sipes and
Geyer, 1997; Ouagazzal et al., 2001; McFarland et al., 2011). However, compounds that lack
psychedelic action (such as lisuride and yohimbine) also disrupt PPI of the acoustic startle in
rodent models (Bell et al., 2003; Swerdlow et al., 2003; Powell et al., 2005; Halberstadt and
Geyer, 2010). Although this raises concerns about the validity of assessing deficits in PPI as

a rodent behaviour model that predicts psychedelic activity, the possibility of cross-species
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measurements of sensorimotor gating supports the use of PPI of startle in the identification
of new antipsychotic medications with special emphasis on attentional deficits present in
schizophrenia patients.
Behaviour models of metabotropic glutamate 2-dependent antipsychotic

action
All antipsychotic drugs currently used in the clinic are dopaminergic and serotonergic
receptor ligands. Relatively recent findings using dissociative (Moghaddam and Adams,
1998) and psychedelic (Gewirtz and Marek, 2000) drugs in preclinical models of
antipsychotic responses led to the first clinical studies with the metabotropic glutamate 2 and
3 (mGlu2/3) receptor orthosteric agonist LY404039 (active compound of LY2140023; Patil et
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al., 2007; orthosteric agonists bind to the same binding site as the endogenous
neurotransmitter glutamate). These data suggested that LY2140023 represents a potential
new approach to treat schizophrenia. However, in two follow-up studies, Eli Lilly and
Company published double-blind phase 2 clinical trials showing that neither LY2140023 nor
olanzapine were more efficacious than placebo (Kinon et al., 2011), which are inconclusive
findings, and that LY2140023 does not separate from placebo whereas the positive control
risperidone was efficacious (Eli Lilly and Company, 2012a). These findings preceded the
press release that announced the decision to stop the on-going phase 3 clinical trial of the
orthosteric mGlu2/3 agonist for the treatment of schizophrenia (Eli Lilly and Company,
2012b). These discouraging findings contrast recent publications with the allosteric positive
modulator of the mGlu2 receptor ADX71149 from Addex Inc. in partnership with Janssen
R&D (Addex Therapeutics, 2012). Allosteric positive modulators bind to a site distinct from
that of the endogenous neurotransmitter; they do not affect basal receptor activity but
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potentiate the effect of orthosteric agonists. The clinical data show safety and tolerability
and demonstrate an effect in negative symptoms of schizophrenia patients (Addex
Therapeutics, 2012). Although promising, more molecular, preclinical and clinical data are
needed to validate whether activation of the mGlu2 receptor may serve as a new approach to
treat this psychiatric disease.
Another question of interest is the therapeutic-like efficacy of different orthosteric mGlu2/3

agonists and allosteric mGlu2 receptor agonists. Most of the preclinical studies assessing the
role of mGlu2 and/or mGlu3 receptors in the antipsychotic-like effects of mGlu2/3 receptor
agonists have been conducted with orthosteric mGlu2/3 receptor agonists such as LY379268
and LY354740 (Gewirtz and Marek, 2000; Klodzinska et al., 2002; Linden et al., 2004;
Winter et al., 2004; Gonzalez-Maeso et al., 2008; Woolley et al., 2008; Uslaner et al., 2009;
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Horiguchi et al., 2011; Jones et al., 2011; Moreno et al., 2011b). At present, there is only one
study describing the antipsychotic-like effects of the orthosteric mGlu2/3 receptor agonist
LY404039 (active compound of its prodrug LY2140023 in clinical trials; Fell et al., 2008).
The authors tested the effects of LY404039 on the hyperlocomotor activity induced by PCP
and amphetamine in mice. While there are limits to the extrapolation of these findings to
humans, only a relatively high dose of LY404039 (10 mg/kg) significantly reduced the PCP-
induced locomotor activity in wild-type mice (Fell et al., 2008). This antipsychotic-like

effect was absent in mGlu2 knockout, but not in mGlu3 knockout, mice. Similar mGlu2-
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dependent effects have been reported with the mGlu2/3 receptor agonist LY379268 (Woolley
et al., 2008). Thus, the effect of LY379268 on the PCP-induced locomotor activity was
observed in wild-type and mGlu3 knockout, but not mGlu2 knockout mice (Woolley et al.,
2008). However, and importantly, the antipsychotic-like effect of LY379268 on PCP-induced
behaviour was seen at doses below 1 mg/kg (Woolley et al., 2008). Consistent with the
hypothesis that mGlu2, and not mGlu3, is necessary for the antipsychotic-like effects of
mGlu2/3 agonists, data with the allosteric mGlu2 agonists biphenyl-indanone A
(Benneyworth et al., 2007) and LY487379 (Galici et al., 2005) show antipsychotic-like
behavioural effects using the psychedelic drug DOB (Benneyworth et al., 2007), the
dissociative drug PCP (Galici et al., 2005) and amphetamine (Galici et al., 2005) as rodent
models of psychosis. Further clinical studies are needed to evaluate the true efficacy and
long-term safety and these agents in schizophrenia patients.
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With regard to the molecular mechanism of action of glutamate antipsychotics, previous

findings suggest that a functional crosstalk between mGlu2 and 5-HT2A receptors is
necessary for the antipsychotic-like effects of LY379268 (Gonzalez-Maeso et al., 2008;
Fribourg et al., 2011; Moreno et al., 2011a, 2012). Thus, it was shown that the antipsychotic-
like effect of LY379268 (5 mg/kg) on the hyperlocomotor behaviour induced by the PCP-
like drug MK801 was mGlu2-dependent and absent in 5-HT2A knockout mice (Fribourg et
al., 2011). The authors also demonstrate that some, but not all, mGlu2/3 receptor agonists
bind mGlu2 receptor in complex with the 5-HT2A receptor and alter the pattern of
heterotrimeric G protein coupling in a way that predicts their antipsychotic-like behavioural
effects (Fribourg et al., 2011). This represents the first biochemical assay that predicts
psychoactive behavioural effects of a variety of serotonergic and glutamatergic compounds
(Fribourg et al., 2011). Whether the antipsychotic-like effects of LY404039 and other
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orthosteric mGlu2/3, and allosteric mGlu2 receptor agonists require expression of the 5-
HT2A receptor remains to be investigated. Nevertheless, examples of non-antipsychotic
drugs that induce antipsychotic-like behaviour in rodents include methysergide, mianserin
and ketanserin (Ninan and Kulkarni, 1998; O’Neill et al., 1998; Fletcher et al., 2011;
Fribourg et al., 2011; Yadav et al., 2011b; Mestre et al., 2013).
Behaviour models of chronic antipsychotic treatment

In schizophrenia patients, antipsychotic drugs are administered chronically (weeks to
months of continuous treatment; Agid et al., 2003). However, most of the animal behaviour
models of antipsychotic action are based on a single administration of the drug to be tested
(Geyer et al., 2012), which raises concerns about the validity of this therapeutic-like
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behaviour. Recent findings have shown that down-regulation of 5-HT2A receptor may be one
of the mechanisms underlying the antipsychotic-like effects induced by chronic treatment
with antipsychotic drugs (Yadav et al., 2011b). The authors assessed the effects of chronic
treatment with antipsychotic drugs (clozapine, olanzapine and haloperidol) and with 5-HT2A
receptor antagonists/inverse agonists (ketanserin, M100907, M11939, SR46349B and
primavanserin) on 5-HT2A receptor protein level and PCP-induced hyperlocomotor activity
(Yadav et al., 2011b). Interestingly, chronic treatment with clozapine and olanzapine, but not
haloperidol, induced down-regulation of 5-HT2A receptor protein in mouse frontal cortex

and decreased the psychosis-like effects of PCP. These effects were not observed after
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chronic treatment with M100907, M11939, SR46349B or primavanserin. Chronic treatment

with the non-antipsychotic ketanserin down-regulated 5-HT2A receptor protein, whereas
PCP induced hyperlocomotion was not affected (Yadav et al., 2011b).
Another approach to determine the therapeutic-like effects of chronic treatment with

antipsychotic drugs is based on the use of LSD as a mouse model of psychosis (Gonzalez-
Maeso et al., 2008; Kurita et al., 2012; Moreno et al., 2013a, b). Administration of
psychedelic 5-HT2A receptor agonists induces expression of the immediate early genes c-
fos, egr-1 and egr-2 in mouse somatosensory cortex (Gonzalez-Maeso et al., 2003,2007;
Moreno et al., 2013a, b). The authors found that chronic (21 d), but not sub-chronic (2 d),
treatment with clozapine eliminates the induction of c-fos, egr-1 and egr-2 by LSD 1 d after
the final injection (Moreno et al., 2013b). The induction of c-fos, egr-1 and egr-2 by LSD
was not affected with chronic treatment with haloperidol. These findings correlate with the
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effect of chronic clozapine, but not chronic haloperidol, on 5-HT2A receptor binding in
mouse somatosensory cortex. Thus, chronic, but not sub-chronic, treatment with clozapine
down-regulated [3H]ketanserin binding, an effect that was not observed after chronic
treatment with haloperidol (Moreno et al., 2013b). These findings suggest that down-
regulation of 5-HT2A receptor is one of the mechanisms underlying the therapeutic effects of
chronic treatment with antipsychotic drugs. Further work is needed to understand the
cellular networks responsible for down-regulation of this receptor with antagonists/inverse
agonists such as clozapine and olanzapine, as well as their sedative effects (McOmish et al.,
2012; Williams et al., 2012).
Rodent models of maternal adverse life-events during pregnancy

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While it is clear that genetics plays an important role in schizophrenia (Stefansson et al.,
2008, 2009; Walsh et al., 2008; Purcell et al., 2009; Vacic et al., 2011), the genetic
mechanisms of transmission are complex as demonstrated by studies of familial segregations
and monozygotic twins. Thus, twin studies have shown that the risk for both identical twins
to develop schizophrenia is 30–50% (see earlier). Such results point toward a significant
contribution of environmental factors in the development of this neurodevelopmental
disease. Interestingly, epidemiological studies repeatedly suggest that maternal
environmental factors during pregnancy, such as pathogen infection (e.g. virus, bacteria and
protozoa; Menninger, 1919; Brown et al., 2001, 2004, 2005; Babulas et al., 2006; Sorensen
et al., 2009; Yudofsky, 2009) and adverse life-events such as famine (Susser et al., 2008),
war (van Os and Selten, 1998; Malaspina et al., 2008) and death or illness in a first-degree
relative (Khashan et al., 2008) increase the risk of schizophrenia in the adult offspring. Also
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shown has been an association between foetal hypoxia or anoxia due to obstetric
complications during labour and delivery and schizophrenia (Buka et al., 1993; Hirshfeld-
Becker et al., 2004; Mittal et al., 2008; Nicodemus et al., 2008). Interestingly, recent
findings demonstrate that mouse models of maternal viral infection and maternal variable
stress may serve as preclinical models for future studies to investigate the mechanisms and
alterations in gene×environment interactions responsible for schizophrenia symptoms.

Radioligand binding assays in post-mortem human brain samples suggest that 5-HT2A
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receptor binding is increased and mGlu2/3 binding is decreased in frontal cortex of untreated
schizophrenic subjects (Gonzalez-Maeso et al., 2008; Moreno et al., 2012; Muguruza et al.,
2012). Similar alterations have been reported in two mouse models of maternal adverse life-
events: influenza virus infection (Moreno et al., 2011b); variable and unpredictable stress
(Holloway et al., 2013). Thus, adult mice born to influenza virus infected mothers show up-
regulation of 5-HT2A receptor and down-regulation of mGlu2/3 receptors (Moreno et al.,
2011b). These biochemical changes correlate with behavioural alterations: increased head-
twitch behaviour induced by the psychedelic drug DOI; decreased effect of LY379268 on
the MK801-dependent locomotor activity (Moreno et al., 2011b). Interestingly, a similar
pattern of biochemical and behavioural changes has been shown in adult mice born to
mothers stressed during pregnancy (Holloway et al., 2013). It has also been suggested that
the existence of epigenetic modifications at the promoter regions of 5-HT2A (Htr2a), mGlu2
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(Grm2) and mGlu3 (Grm3) genes correlates with this pattern of expression and their
behavioural function (Matrisciano et al., 2012). As reviewed earlier, both maternal infection
and maternal severe stress during pregnancy are implicated as having an aetiological role in
schizophrenia. Numerous experimental investigations have provided robust evidence that
adverse life experiences profoundly modulate immune cell functions (Maes et al., 1998;
Steptoe et al., 2001; Vanbesien-Mailliot et al., 2007; Garcia-Bueno et al., 2008) and it is
thought that activation of the maternal immune system produces cytokines and chemokines
that ultimately alter neurogenesis and migration of neurons during brain development,
contributing to schizophrenia risk (Nawa and Takei, 2006; Bilbo and Schwarz, 2009;
Deverman and Patterson, 2009). Further investigation is necessary to understand the
gene×environment interactions as well as the contribution of specific components of the
maternal immune system responsible for schizophrenia and other neurodevelopmental
disorders in the adult offspring.
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Conclusions
In this review, we summarize some of the current knowledge of animal models of psychosis
and antipsychotic action. The antipsychotics currently used in clinical practice are designed
to treat the symptoms of the disease. As yet, the underlying mechanisms responsible for the
onset of psychosis in schizophrenia patients remain largely unknown. About 30% of the
patients are considered treatment resistant and will continue to experience schizophrenia
symptoms despite the use of antipsychotic drug treatment. Recent preclinical (Kurita et al.,
2012) and clinical (Citrome et al., 2004; Meltzer et al., 2011) findings have proposed the use
of epigenetic drugs to inhibit histone deacetylation in order to improve the clinical efficacy
of the currently available antipsychotic drugs. Although psychedelic and dissociative drugs
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as a model of schizophrenia have limitations, some of the findings summarized in this

review suggest that their use in animal models may serve as a tool to find new antipsychotic
drugs for treatment and also prevention of schizophrenia and other psychotic disorders.
Acknowledgements
This study was supported by NIH R01 MH084894, Dainippon Sumitomo Pharma, NARSAD and The Mortimer D.
Sackler Foundation (J.G.M.).

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NIH Preclinical Models of Antipsychotic Drug Action

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Preclinical models of antipsychotic drug action

Antipsychotic drugs; epigenetics; lysergic acid diethylamide; metabotropic glutamate 2 receptor;

attempts in patients with schizophrenia as compared with approximately 5% in the general

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

our understanding, based on rodent models of psychedelic or dissociative drug exposure, of

Pharmacological models of psychosis and antipsychotic drug action

drugs in animals as a preclinical model of psychosis-like behaviour.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

Modulation of locomotor activity

chlorpromazine), antipsychotics on the hyperlocomotor response induced by dissociative

antagonists such as volinanserin (M100907) reduce the locomotor hyperactivity induced by

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

involved in the therapeutic-like effects of atypical antipsychotics, using hyperlocomotor

The psychedelic 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) has

model of hallucinogenic potential in humans. Using pharmacological tools in rats, it has

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

A long-lasting question in neuropharmacology has been the molecular mechanisms

Modulation of psychedelic-dependent head-twitch behaviour has also been tested as a model

of antipsychotic action (see later for discussion).

Prepulse inhibition of startle

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

Behaviour models of metabotropic glutamate 2-dependent antipsychotic

Another question of interest is the therapeutic-like efficacy of different orthosteric mGlu2/3

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

With regard to the molecular mechanism of action of glutamate antipsychotics, previous

Behaviour models of chronic antipsychotic treatment

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

chronic treatment with M100907, M11939, SR46349B or primavanserin. Chronic treatment

Another approach to determine the therapeutic-like effects of chronic treatment with

Rodent models of maternal adverse life-events during pregnancy

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

as a model of schizophrenia have limitations, some of the findings summarized in this

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

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schizophrenia: implications for mortality. J Psychopharmacol. 2010; 24:91–118. [PubMed:

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healthy human subjects following repeated exposure to ketamine. Psychopharmacology (Berl).

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

Gleason SD, Shannon HE. Blockade of phencyclidine-induced hyperlocomotion by olanzapine,

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R,

nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory

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humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-

by 5-HT(2A) receptors in the forebrain. Neuropsychopharmacology. 2012; 37:2747–2755.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

valproic acid augmentation. J Clin Psychiatry. 2011; 72:1602–1610. [PubMed: 21813074]

Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2016 April 19.

expression induced by dizocilpine. J Pharmacol Exp Ther. 1998; 287:839–846. [PubMed:

394. [PubMed: 21482187]

schizophrenia: implications for treatment. Br J Pharmacol. 2008; 153(Suppl. 1):S465–S470.

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