Phencyclidine and genetic animal models of schizophrenia developed in relation to the glutamate hypothesis.
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.
Enomoto
T
T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Noda
Y
Y
Nabeshima
T
T
D000818:Animals; D001522:Behavior, Animal; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D003071:Cognition; D004195:Disease Models, Animal; D005684:Gait; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007266:Inhibition, Psychological; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020890:Neuregulin-1; D010622:Phencyclidine; D049368:Receptors, Lysophosphatidic Acid / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D012565:Schizophrenic Psychology; D012919:Social Behavior
C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D049368:Receptors, Lysophosphatidic Acid; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019703:Calcineurin; D010622:Phencyclidine