Phencyclidine and genetic animal models of schizophrenia developed in relation to the glutamate hypothesis.

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) produces a schizophrenia-like psychosis in humans, including positive symptoms, negative symptoms, and cognitive dysfunction. PCP-treated animals show hyperlocomotion, social behavioral deficits, enhanced immobility in forced swimming, sensorimotor gating deficits, and cognitive dysfunctions, some of which persist after withdrawal from repeated treatment. Repeated PCP treatment also induces neurochemical and neuroanatomical changes. Genetic animal models based on the glutamate hypothesis of schizophrenia, such as NMDA receptor subunit knockdown or knockout mice, also exhibit schizophrenia-like behaviors. These PCP and genetic models are useful for evaluating novel therapeutic candidates and studying pathological mechanisms of schizophrenia.

Study at a glance

Abstract

In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, PCP-treated animals have been utilized as an animal model of schizophrenia. PCP-treated animals exhibit hyperlocomotion as an index of positive symptoms, and 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 deficit 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 neuronanatomical changes. Recently, genetic approaches based on "the glutamate hypothesis of schizophrenia" have been used to develop animal models of schizophrenia. NMDA receptor subunit zeta1 knockdown, epsilon1 knockout (KO) and zeta1 point mutant mice exhibiting a hypofunction of NMDA receptors show hyperlocomotion, social behavioral deficit, sensorimotor gating deficit or cognitive dysfunction. Forebrain-specific calcineurin KO, neuregulin 1 heterozygous KO and lysophosphatidic acid 1 receptor KO mice can also serve as animal models of schizophrenia. These findings suggest that PCP and genetic animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.