Effects of repeated phencyclidine administration on adult hippocampal neurogenesis in the rat.

Repeated injections of phencyclidine (PCP, 7.5 mg/kg) in rats cause a 23% decrease in the number of newly born cells in the dentate gyrus of the hippocampus 24 hours after the last injection, but cell counts return to normal within one week. The survival of cells already formed is not affected. PCP also produces stereotyped behaviors that increase with repeated doses, while ataxia and backpedaling behaviors decrease. These transient disruptions in cell proliferation may relate to behavioral abnormalities induced by PCP, though whether they contribute to behavioral sensitization or result from adaptation to the drug's effects remains unclear.

Study at a glance

Abstract

Dysfunctional maturation of neural networks, particularly hippocampus-prefrontal networks, may be of particular interest in determining the pathophysiology of schizophrenia. Phencyclidine (PCP)-induced symptoms in humans appear to offer a more complete model of schizophrenia than do amphetamine-induced symptoms. This study investigated the effects of intermittent i.p. injections of PCP (7.5 mg/kg) on cell proliferation and survival of granule cells in the dentate gyrus of the rat brain using quantitative immunohistochemical techniques for 5-bromo-2'-deoxyuridine (BrdU)-positive cells. After repeated PCP injection for 14 days, mean scores for stereotyped behavior increased with the number of injections, while scores for ataxia and backpedaling as serotonergic behaviors gradually decreased. The number of BrdU-positive cells decreased by 23% in the subgranular zone of the dentate gyrus by 24 h after repeated injections. However, decreased levels of BrdU-positive cells returned to control levels within 1 week. Differentiation of newly formed cells was not influenced. Repeated PCP administration after BrdU injection did not exert any effects on survival of newly generated cells. These findings suggest that transient disturbances of cell proliferation in the dentate gyrus occur under PCP-related behavioral abnormalities. Whether disturbed cell proliferation would thus be closely implicated in the development of behavioral sensitization induced by PCP administration is unclear, but this would possibly result from adaptation to new pharmacological conditions under behavioral sensitization or stressful conditions of PCP-related abnormal behaviors. Further studies are required to elucidate the biological significance of hippocampal neurogenesis in the mechanisms underlying the development of cognitive dysfunctions and the psychosis of schizophrenia.