Phencyclidine dependence: the relationship of dose and serum concentrations to operant behavioral effects

The dependence-producing properties of 10 days of chronic i.v. infusions of phencyclidine (PCP) and the relationship between PCP serum concentrations and behavioral effects were studied in Sprague-Dawley rats. For dependence studies, rats were trained to respond for food under a fixed-ratio 30 schedule during half-hour response periods every 6 hr. After training, implantation of jugular catheters, and restabilization of behavior, the rats were infused with PCP.HCl at 3.2, 5.6, 10.0 or 17.8 mg/kg/day (n = 5 or 6 per dose). The two higher doses initially decreased response rates, but tolerance developed within 4 to 5 days. When PCP infusions were terminated, dose-dependent decreases in session response rate occurred in the three highest dose groups (P less than .05). Mild, overt signs of abstinence were observed only in the highest dose group. Response rates returned to base line within 2 to 3 days after stopping PCP infusions. PCP serum concentrations in rats infused with 10 mg of PCP.HCl/kg/day for 10 days were stable from hour 24 to day 10 (mean steady-state concentration (+/- S.D.) = 97 (+/- 20) ng of PCP/ml; n = 4). The average terminal elimination half-life after stopping infusions on day 10 was 4.6 hr. Comparison of the average response rates with the average serum concentrations showed that during the first 24 hr of infusions, the rate of responding for food decreased as PCP concentrations increased; however, once the animals became tolerant to PCP there was no relationship. In contrast, during the first 24 hr after stopping infusions, response rates decreased as serum concentrations decreased.