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

RATIONALE: 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. OBJECTIVES: This study aims to systematically investigate the effects of systemically administered clozapine, metoclopramide, haloperidol and risperidone during free operant response acquisition and performance. METHODS: Following magazine training, food-restricted male Wistar rats lever pressed for food reward in 15 min daily operant conditioning sessions. RESULTS: 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. CONCLUSIONS: 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.

Reinforcer devaluation by extinction depends on the food restriction protocol.

A common feature of reinforcer devaluation studies is that new learning induces the devaluation. The present study used extinction to induce new learning about the conditioned reinforcer in a heterogeneous chain schedule. Rats pressed a lever in a heterogeneous chain schedule to produce a conditioned reinforcer (light) associated with the opportunity to obtain an unconditioned reinforcer (food) by pulling a chain. The density of food reinforcement correlated with the conditioned reinforcer was varied in a comparison of continuous and variable-ratio reinforcement schedules of chain pulling; this had no noticeable effect on conditioned reinforcer devaluation produced by extinction of chain pulling. In contrast, how rats were deprived appeared to matter very much. Restricting meal duration to 1h daily produced more lever pressing during baseline training and a greater reductive effect of devaluation on lever pressing than restricting body weight to 80% of a control rat's weight, which eliminated the devaluation effect. Further analysis suggested that meal-duration restriction may have produced devaluation effects because it was more effective than weight restriction in reducing rats' body weights. Our results exposed an important limitation on the devaluation of conditioned reinforcers: slight differences in food restriction, using two commonly employed food-restriction procedures, can produce completely different interpretations of reinforcer devaluation while leaving reinforcer-based learning intact.

Amphetamine-induced enhancement of responding for conditioned reward in rats: interactions with repeated testing.

RATIONALE: The mesolimbic dopamine system underlies the ability of reward-related stimuli to control operant behavior. Previous work has shown that amphetamine potentiates operant responding for conditioned rewards (CRs). OBJECTIVES: Here, we asked whether the profile of this amphetamine-produced potentiation changes with repeated CR presentation, i.e., as the CR is being extinguished. METHODS: Amphetamine (0-1.0 mg/kg, i.p.), administered over four daily sessions using a Latin square design, dose-dependently increased lever pressing for a 'lights-off' stimulus previously paired with food in rats. RESULTS: The amphetamine-produced enhancement of responding for CR was significantly modulated with repeated CR exposure: it was strongest on day 1 and became less pronounced in subsequent sessions whereas the CR effect persisted. In further experiments, rats receiving LiCl devaluation of the primary reward failed to show a significant reduction in the amphetamine-produced enhancement of responding for CR. CONCLUSIONS: The nature of the dissociable effects of amphetamine on responding for CR versus the CR effect itself remains to be elucidated.

Regional differences in the action of antipsychotic drugs: implications for cognitive effects in schizophrenic patients.

Antipsychotic drugs (APDs) have been classified as typical or atypical based on their liability to produce extrapyramidal side effects: atypical APDs are less likely to produce extrapyamidal side effects at therapeutic doses. Evidence from immediate early gene immunohistochemical, electrophysiological, microdialysis, imaging, and behavioral studies suggests that typical APDs preferentially affect the nucleus accumbens (NAc) and the dorsal striatum while atypical APDs preferentially affect the NAc and medial prefrontal cortex (PFC). We review some of this evidence and then discuss studies that have employed cognitive tasks shown previously to depend on dorsal striatal or medial PFC function in schizophrenic patients treated with typical or atypical APDs. Results revealed that patients treated with typical APDs displayed deficits in cognitive tasks that depended on the dorsal striatum but not in tasks that depended on the medial PFC and that those treated with atypical APDs displayed deficits in cognitive tasks that depended on the medial PFC but not in cognitive tasks that depended on the dorsal striatum. These findings suggest that some of the cognitive deficits seen in schizophrenic patients may be related to the medications that are used to treat them.