Time-dependent sensitization of antipsychotic effect in adolescent male and female rats

Abstract

Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change following even one single drug exposure. The present study examined whether one or two exposures of haloperidol, olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats, and whether such a change vary between sexes. Adolescent Sprague-Dawley rats (<40days old) were first treated with one single injection of haloperidol (0.05 and 0.1mg/kg, sc), clozapine (10.0 and 20.0mg/kg, sc), 2 injections of olanzapine (1.0 and 2.0mg/kg, sc) or vehicle, and tested in a conditioned avoidance response (CAR) model or a PCP (3.20mg/kg, sc)-induced hyperlocomotion model to assess the drug's antipsychotic-like behavioral effects. One or three weeks later, rats were challenged with the drug and their avoidance responses and the PCP-induced hyperlocomotion were re-assessed. One-trial haloperidol and 2-trial olanzapine induced a sensitization, while 1-trial clozapine induced a tolerance effect. The 1-trial haloperidol sensitization was significantly higher at the 3-week time point than at 1-week point, especially in the females. Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent increase in both sex groups. Olanzapine sensitization in the PCP model showed a time-dependent change in a sex-dependent fashion. Overall, the time-dependent antipsychotic sensitization and tolerance can be demonstrated in adolescent animals. Many pharmacological (e.g. specific drugs, drug doses), individual (e.g. male versus female) and environmental (e.g. specific behavioral models) factors play a role in the modulation of the strength of antipsychotic sensitization and tolerance.

Keywords: Clozapine; Conditioned avoidance response; Haloperidol; Olanzapine; Phencyclidine; Sensitization; Time-dependent sensitization; Tolerance.