Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: Involvement in frontostriatal cognitive deficits

Long-term exposure to the psychotomimetic drug phencyclidine produces prefr ontal cortical cognitive and dopaminergic dysfunction in rats and monkeys, effects possibly relevant to the frontal cortical impairments of schizophre nia. In the present study, the effects of subchronic phencyclidine administ ration (0.3 mg/kg twice-daily for 14 days) on monoamine systems in the monk ey brain were examined and related to cognitive performance on an object re trieval/detour task, which has been linked with frontostriatal function. Lo ng-term (14 days) administration of phencyclidine resulted in a marked and persistent reduction in dopamine utilization in the frontal cortex. Moreove r, the degree of cognitive impairment in phencyclidine-treated monkeys corr elated significantly with the magnitude of dopaminergic inhibition within t he dorsolateral prefrontal cortex and prelimbic cortex. No specific correla tion was measured for dopamine utilization in other cortical regions or for indices of serotonin transmission in any brain region. These data show that repeated exposure to phencyclidine reduces prefrontal cortical dopamine transmission, and this inhibition of dopaminergic functio n is associated with performance impairments on a task sensitive to frontos triatal cognitive dysfunction. Thus, the cognitive deficits of phencyclidin e-treated monkeys, as in schizophrenia, appear to be mediated, in part, by reduced dopaminergic function in specific subregions of the frontal cortex. (C) 1999 IBRO. Published by Elsevier Science Ltd.