Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats

Phencyclidine (PCP) produces psychotomimetic effects in humans that resembl e schizophrenia symptoms. In an effort to screen compounds for antipsychoti c activity, preclinical researchers have investigated whether these compoun ds block PCP-induced behaviors in animals. In the present study, the atypic al antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled-unsignalled diffe rential-reinforcement-of-low-rates (DRL) procedures. PCP produced distincti ve effects in each task: it substituted for the training dose in PCP discri mination and it increased the number of responses with short (<3 s) interre sponse times as well as increasing overall response rates in the DRL schedu le. Acute dosing with clozapine failed to alter the behavioral effects of P CP in either procedure even when tested up to doses that produced pharmacol ogical effects alone. These results suggest that acute dosing with clozapin e would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination pro cedures in animals to screen for antipsychotic potential. Since chronic dos ing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in c ombination with PCP. (C) 2000 Elsevier Science Ltd. All rights reserved.