Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs.

The classical neuroleptic drugs haloperidol and pimozide have a strong disruptive effect on the acquisition of conditioned avoidance responding (CAR), yet have relatively little impact on the performance of previously acquired responses. Separate experiments compared the effects of haloperidol, two atypical neuroleptics, thioridazine and clozapine, and a substituted benzamide, metoclopramide, on one-way avoidance by rats. Thioridazine (10-50 mg/kg) and clozapine (1.25-10.0 mg/kg) disrupted both acquisition and performance of CAR. In contrast, haloperidol (0.075-0.150 mg/kg) and metoclopramide (5.0-7.5 mg/kg) completely blocked the acquisition of CAR, yet initially produced only a slight disruption in the performance of a previously acquired response. The ineffectiveness of the atypical neuroleptics in producing a complete disruption of acquisition of CAR may be due to the anticholinergic properties of these drugs. Alternatively, the differences between metoclopramide and the atypical neuroleptics may be due to a preferential effect of metoclopramide on striatal or amygdaloid dopamine neurotransmission. These results suggest that caution should be exercised in using CAR as an animal model for assessing the antipsychotic potential of new pharmacological agents.