Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex

Background: The increase in glutamate efflux in the prefrontal cortex by th e psychotomimetic drugs phencyclidine (PCP) and ketamine may produce the do paminergic and some of the behavioral effects of these drugs. Here, we exam ined whether antipsychotic drugs influence this increase. Methods: The effect of haloperidol, clozapine or the 5-HT2A antagonist, M10 0907, on PCP-induced increase in cortical glutamate efflux was examined by, microdialysis. Because previous studies had suggested that M100907 attenua tes some behavioral effects of PCP, we also examined the effect of M100907 on PCP-induced cortical and accumbal dopamine activation while making conco mitant measures of locomotion and stereotypy. Results: Haloperidol, clozapine or M100907 did not significantly block hype rglutamatergic effects of PCP. M100907 was ineffective in inhibiting the do paminergic and motoric effects of PCP. Conclusions: These results contrast previous findings with glutamatergic dr ugs, such as AMPA antagonists or group II metabotropic glutamate agonists, that blocked glutamatergic and motoric effects of PCP. Thus, the PCP glutam ate activation model lacks predictive validity, for conventional antipsycho tics; however, this model may, be useful for design of novel classes of dru gs that target those symptoms of schizophrenia that are not generally, trea ted with monoamine-based antipsychotics. (C) 2001 Society of Biological Psy chiatry.