Effect of environmental cues on the behavioral efficacy of haloperidol, olanzapine, and clozapine in rats

Previous studies have reported that context can powerfully modulate the inhibitory effect of an antipsychotic drug on phencyclidine (PCP)-induced hyperlocomotion (a behavioral test used to evaluate putative antipsychotic drugs). The present study investigated the experimental conditions under which environmental stimuli exert their influence through associative conditioning processes. Experiment 1 examined the extent to which previous antipsychotic treatment in the home cages affected a drug's ability to inhibit PCP-induced hyperlocomotion in novel motor activity test apparatus. Five days of repeated haloperidol (0.05mg/kg, subcutaneously) and olanzapine (2.0mg/kg, subcutaneously) treatment in the home cages still potentiated their inhibition of PCP-induced hyperlocomotion (i.e. sensitization) assessed in a new environment, whereas the clozapine (10.0mg/kg, subcutaneously) treatment enhanced the development of clozapine tolerance, indicating a lack of environmental modulation of antipsychotic efficacy. Experiment 2 assessed the impact of different numbers of antipsychotic administrations (e.g. 4, 2 or 0), in either the home environment or test environment, on a drug's ability to inhibit PCP-induced hyperlocomotion. Repeated administration of clozapine (5.0mg/kg, subcutaneously) or olanzapine (1.0mg/kg, subcutaneously) for 4 consecutive days, irrespective of where these treatments occurred, led to a similar level of inhibition of PCP-induced hyperlocomotion. However, 4-day haloperidol (0.03mg/kg, subcutaneously) treatment in the test apparatus led to significantly higher inhibition than a 4-day home-cage treatment. Thus, more exposures to the test environment under the influence of haloperidol (but not clozapine or olanzapine) caused a stronger inhibition than fewer exposures, indicating a strong environmental modulation. Collectively, these findings suggest that previous antipsychotic treatment in one environment could alter later antipsychotic-like response assessed in a different environment under certain test conditions. Therefore, whether the circumstances surrounding antipsychotic drug administration have a powerful effect on the expression of antipsychotic-like efficacy is dependent on specific experimental and drug treatment factors.