CLOZAPINE REVERSES THE SPATIAL WORKING-MEMORY DEFICITS INDUCED BY FG7142 IN MONKEYS

The atypical neuroleptic, clozapine, has been shown to have encouragin g, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA ) dysregulation. The current study examined the effects of acute cloza pine pretreatment on the spatial working memory deficits induced by th e pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys t hrough excessive DA receptor stimulation in the PFC (Murphy et al. 199 6). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most anima ls. Clozapine alone produced a dose-related impairment in delayed resp onse performance. These results from nonhuman primates suggest that th e clozapine doses commonly used to treat schizophrenia may not be opti mal for treating the PFC cognitive deficits associated with this illne ss. (C) 1997 American College of Neuropsychopharmacology.