Sex differences in aripiprazole sensitization from adolescence to adulthood

- Sex differences exist in response to adolescent ARI treatment into adulthood.
- Adolescent ARI treatment enhances inhibition of PCP-induced hyperlocomotion.
- ARI reduces PCP-induced increases in motor activity with more robust effects in males as compared to females.

The present study investigated the potential sex differences in repeated aripiprazole (ARI) treatment-induced behavioral sensitization from adolescence to adulthood, and to determine whether ARI sensitization can be transferred to olanzapine (OLZ) and/or clozapine (CLZ) using the conditioned avoidance response (CAR) and phencyclidine-induced (PCP) hyperlocomotion tests of antipsychotic activity. Male and female Sprague-Dawley adolescence rats (P46) were first treated with ARI (10 mg/kg) for 5 consecutive days (P46-50) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion. After they became adults (> P68), rats were challenged with ARI (1.5 mg/kg, sc) (P70), OLZ (0.5 mg/kg, sc; P73), CLZ (5 mg/kg, sc; P76) and again with ARI (1.5 mg/kg, sc; P84) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion again. During the drug treatment period in adolescence, repeated ARI treatment suppressed avoidance response, inhibited the PCP-induced hyperlocomotion, and these effects were progressively increased across the 5-day period in both males and females, confirming the induction of ARI sensitization. On the challenge days, rats previously treated with ARI in adolescence also had significantly lower avoidance and lower PCP-induced hyperlocomotion than the previous vehicle rats, confirming the expression of ARI sensitization and its persistence into adulthood. More importantly, female rats made significantly more avoidances than males in both ARI and vehicle groups, indicating higher sensitivity to the acute and long-term effects of ARI. Further, on the OLZ and CLZ challenge days, prior ARI treatment seemed to increase sensitivity to OLZ exposure, however, this increase was not significant. Similarly, rats also showed an ARI sensitization to OLZ and CLZ on challenge days. Collectively, results from this experiment demonstrated a sex difference in response to ARI and enhanced inhibition of PCP-induced hyperlocomotion in animals that were pretreated with ARI as compared to controls.