Phencyclidine animal models of schizophrenia: Approaches from abnormality of glutamatergic neurotransmission and neurodevelopment

Abstract

In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.

Introduction

Schizophrenia is a severe psychiatric disease that has a lifetime prevalence of 1% in most of the populations studied (Rossler et al., 2005). Schizophrenic patients show positive symptoms (e.g., hallucinations, delusions and thought disorder), negative symptoms (e.g., deficits in social interaction, emotional expression and motivation) and cognitive dysfunction (e.g., impairments of attention and working memory) (Pearlson, 2000). The glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses (Carlsson et al., 1997). It has originated from the observation that intoxication of phencyclidine (PCP), which is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, closely mimics schizophrenia (Javitt and Zukin, 1991). In clinical trial, acute PCP administration causes transient schizophrenic psychosis in normal volunteers and exacerbates symptoms in schizophrenic patients (Luby et al., 1959, Javitt and Zukin, 1991). Interestingly, the prolonged ingestion of PCP induces long-lasting neuropsychological deficits for several weeks (Rainey and Crowder, 1975, Allen and Young, 1978, Cosgrove and Newell, 1991).

Meanwhile, several lines of evidence suggest that the NMDA receptor is involved in the pathogenesis of schizophrenia. Postmortem studies in schizophrenic patients have identified abnormalities of NMDA receptor expression (Akbarian et al., 1996, Dracheva et al., 2001) and phosphorylation (Emamian et al., 2004) in the prefrontal cortex, which is considered to be the major region contributing to the pathophysiology of negative symptom and cognitive dysfunction in schizophrenia (Weinberger, 1988). Some genetic analyses have disclosed that single nucleotide or dinucleotide-repeated polymorphisms of the NMDA receptor subunit gene increase susceptibility to schizophrenia (Ohtsuki et al., 2001, Rice et al., 2001, Itokawa et al., 2003).

Many attempts have been made to develop animal models of schizophrenia by using NMDA receptor antagonists, such as PCP, ketamine and dizocilpine. Jentsch and Roth (1999) have proposed that the effects of chronic, rather than acute, exposure to PCP may better represent some facets of schizophrenia. In animal experiments, some of the neurochemical, neuroanatomical and behavioral alternations observed after withdrawal from repeated PCP treatment are correlated with clinical observations. Therefore, withdrawal from repeated PCP treatment might provide a valuable animal model of schizophrenia. In addition, the disorder of neurodevelopment is proposed as a trigger of the onset of schizophrenia (Lewis and Levitt, 2002, Raedler et al., 1998). Perinatal NMDA antagonist treatment developed a neurodevelopment model of schizophrenia. In this review, we focused on behavioral studies in PCP animal models of schizophrenia induced by acute and chronic treatments in adulthood and perinatal treatment and summarized recent evidence from several investigators.