Relationship between the development of behavioral tolerance and the biodisposition of phencyclidine in mice.

Mice trained on a differential reinforcement of low rate 10-sec schedule (DRL 10) were treated daily with either IP saline or 10 mg/kg of phencyclidine hydrochloride (PCP). After 21 consecutive days of treatment, dose-effect determinations for PCP were obtained in both groups. Chronic treatment with PCP resulted in approximately 1.5-fold development of tolerance to the PCP-induced reduction of reinforcement rate. Following completion of the dose-effect determinations, the mice were treated for an additional 13 days with either saline or PCP (10 mg/kg, IP). On the fourteenth day, the biodisposition of 3H-PCP-HCl (10 mg/kg, IP) was studied in both groups. The ratio of the brain levels of PCP in the saline-trained animals to that in the PCP-trained animals was 1.3 to 1 which accounted in large part for the development of tolerance. It appears that dispositional factors are involved in the development of tolerance of mice to the disruptive effects of PCP on DRL performance.