Repeated ingestion of phencyclidine by humans induces enduring schizophrenic symptomatology, particularly cognitive dysfunction. In the presently described series of experiments, the neurochemical and cognitive consequences of subchronic phencyclidine administration in the rat were explored. Repeated phencyclidine exposure led to a selective reduction in basal and stress-evoked dopamine utilization in the prefrontal cortex. In addition, rats previously subchronically-treated with phencyclidine were impaired on performance of a spatial working memory task in a delay-dependent manner. Importantly, these dopaminergic and cognitive deficits were observed after withdrawal from phencyclidine, and as such, the neurochemical and behavioral effects were due to drug-induced neurobiological changes rather than direct drug effects. These biochemical and behavioral data show that repeated phencyclidine administration induces prefrontal cortical cognitive deficits in rats, as in humans, and offer a biochemical perspective of the neural substrate underlying this cognitive impairment: inhibition of mesocortical dopamine neurons. Thus, these data may have relevance to psychiatric disorders involving prefrontal cortical dopaminergic hypoactivity and cognitive dysfunction, as has been hypothesized in schizophrenia.

The present study examined delta 9-tetrahydrocannabinol (THC)-induced alterations in monoamine transmission in the rat forebrain as well as the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on the monoamine response to THC. Activation of dopamine (DA) and norepinephrine (NE) but not serotonin (5-HT) turnover in the prefrontal cortex (PFC) was observed after THC (5 mg/kg i.p.) administration. Both enantiomers of HA966 completely prevented the effects of THC on PFC DA turnover and partially blocked the THC-induced rise in NE metabolism. The cognitive consequences of THC exposure were also examined. THC significantly impaired spatial working, but not reference, memory in rats, and this effect was ameliorated by HA966. Thus, HA966 prevents the THC-induced increases in PFC DA turnover and impairments of prefrontal cortical working memory function. Furthermore, these data suggest that cognitive impairments displayed by marijuana self-administering humans may be related to PFC DA hyperactivity and that HA966 may prevent this effect.