PHENCYCLIDINE INCREASES FOREBRAIN MONOAMINE METABOLISM IN RATS AND MONKEYS - MODULATION BY THE ISOMERS OF HA966

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has ps ychotomimetic properties in humans and activates the frontal cortical dopamine innervation in rats, findings that have contributed to a hype rdopaminergic hypothesis of schizophrenia. In the present studies, the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced changes in monoamine metabolism in the forebrain of ra ts and monkeys were examined, because HA966 has been shown previously to attenuate stress- or drug-induced activation of dopamine systems. I n rats, PCP (10 mg/kg, i.p.) potently activated dopamine (DA) turnover in the medial prefrontal cortex (PFC) and nucleus accumbens. Serotoni n utilization was also increased in PFC. Pretreatment with either R-()HA966 (15 mg/kg, i.p.) or S-(-)HA966 (3 mg/kg, i.p.) partially blocke d PCP-induced increases in PFC DA turnover, whereas neither enantiomer altered the effect of PCP on DA turnover in the nucleus accumbens or the PCP-induced increases in serotonin turnover in PFC. PCP (0.3 mg/kg , i.m.) exerted regionally selective effects on the dopaminergic and s erotonergic innervation of the monkey frontal cortex, effects blocked by pretreatment with S-(-)HA966 (3 mg/kg, i.m.). Importantly, these da ta demonstrate that in the primate, PCP has potent effects on dopamine transmission in the frontal cortex, a brain region thought to be dysf unctional in schizophrenia. In addition, a role for S-(-)HA966 as a mo dulator of cortical monoamine trans mission in primates is posited.