Differential effects of clozapine, metoclopramide, haloperidol and risperidone on acquisition and performance of operant responding in rats.

Abstract

Prior research has not systematically investigated the effects of systemic antipsychotic drugs on operant response acquisition, specifically their behavioural microstructure, reinforcement blunting and relative potency in acquisition compared to performance once operant responding has stabilized. This study aims to systematically investigate the effects of systemically administered clozapine, metoclopramide, haloperidol and risperidone during free operant response acquisition and performance. Following magazine training, food-restricted male Wistar rats lever pressed for food reward in 15 min daily operant conditioning sessions. All drugs suppressed operant response acquisition and performance. Risperidone and metoclopramide, but not clozapine or haloperidol, suppressed operant responding more potently during acquisition than performance. The dopamine D2-like receptor antagonists haloperidol and metoclopramide that affect the ventral and dorsal striatum blunted reinforcement and decreased inactive lever presses in acquisition. In contrast, the atypical antipsychotics clozapine and risperidone that affect the ventral striatum and prefrontal cortex failed to decrease inactive lever presses during acquisition, suggesting a possible decision-making deficit. Haloperidol decreased active lever pressing over performance days. The drugs did not appear to affect rats' sensitivity to active lever press outcome, even though they suppressed active lever pressing. Results suggest that reinforcement impact during operant acquisition is dependent on dopamine D2 receptors while drugs affecting, among other areas, the prefrontal cortex produce a deficit in ability to suppress inactive lever press responses.