Augmentation of locomotor activity by chronic phencyclidine is associated with an increase in striatal NMDA receptor function and an upregulation of the NR1 receptor subunit

Phencyclidine (PCF) is a drug of abuse that produces schizophrenia-like sym ptoms in humans and increases locomotor activity and stereotypic behavior i n rodents. PCP-induced alteration in rat locomotor activity is thought to b e mediated by an inhibition of N-methyl-D-aspartate (NMDA) receptors in the striatum and other brain regions. In this study, rats treated chronically with PCP (20 mg/kg once per day for 5 days) showed a marked increase in loc omotor activity following a PCP challenge (3.2 mg/kg) administered after ei ther 3 or 8 days of withdrawal. In biochemical assays, the release of stria tal [C-14]GABA by NMDA was enhanced by about 77% by chronic PCP treatment, whereas [H-3]ACh release was increased by about 31% in tissue from PCP-trea ted rats. Even though binding experiments with 1- [1-(2-thiehyl)cyclohexyl] piperidyl-3,4 H-3(N) ([H-3]TCP) showed no alteration in the Kd or Bmax in whole striatum, quantitative immunocytochemical experiments found an upregu lation in the NR1 subunit in the cell bodies and neuropil of cortical and s triatal regions of the forebrain following chronic PCP treatment. An increa se in the size of NR1-immunoreactive cells in the forebrain was also observ ed following chronic PCP treatment. Together, these data may help in unders tanding the mechanisms underlying the adaptive response to chronic reductio n in glutamatergic NMDA transmission that has been postulated to be involve d in the etiology of schizophrenia. Synapse 31:229-239, 1999. (C) 1999 Wile y-Liss, Inc.