Tolerance to the reinforcing effects of cocaine in a progressive ratio paradigm.

This experiment used rats to test whether a regimen of chronic cocaine would produce tolerance to cocaine i.v. self-administration under a progressive ratio (PR) schedule of reinforcement. Under this PR schedule, an increasing number of responses was required to complete the ratio for each subsequent cocaine injection, and failure to complete the required ratio for the next injection within 1 h of the previous cocaine injection terminated the session. The number of injections taken in the session was termed the breaking point and used as the dependent variable. Rats were trained under this schedule until breaking point values were stable, after which cocaine dose-effect data were obtained: the breaking point increased as the dose of cocaine increased. Subsequently, rats were assigned to one of two groups for 7 days of chronic treatment: one group was infused with cocaine (18 mg/kg, given over 20 min once every 8 h) and the other group received 0.9% saline. Following termination of chronic treatment, cocaine dose-effect data were redetermined in both groups. Chronic cocaine treatment significantly decreased breaking point values across the entire dose-effect curve, although the effect was observed in only four of seven subjects. In contrast, chronic saline treatment produced no significant effect on the breaking point measures. Following a further 5 days of recovery from chronic treatment, cocaine dose-effect data were redetermined in both groups; these curves were essentially identical to those obtained before chronic treatments. These data support the hypothesis that tolerance occurs to the reinforcing effects of cocaine, as measured by a decrease in the breaking point, at least for a subset of animals.