Tolerance to and residual effects of cocaine in squirrel monkeys depend on reinforcement-schedule parameter.

Lever pressing by 4 squirrel monkeys was maintained under a three-component multiple fixed-ratio schedule of food presentation; components differed with respect to ratio size. For each monkey, acute administration of cocaine (0.03 to 1.3 mg/kg, i.m.) produced dose-dependent decreases in overall response rate in each component. During repeated daily administration of 1.0 mg/kg of cocaine, tolerance developed to the rate-decreasing effects under each of the ratio contingencies, but developed to a greater extent and was evident in earlier parts of sessions for performance under the smaller ratios. Response rates of 2 monkeys increased above nondrug control levels despite the putative reinforcer not being consumed during the session. When saline or a smaller dose of cocaine was substituted for 1.0 mg/kg, response rates often were suppressed below nondrug control-level responding. This suppressive effect was observed in each monkey and was more likely to be observed and/or to be of greater magnitude in large-ratio components for 3 of the 4 monkeys. When saline was administered chronically at the end of the chronic-drug phase, response rates remained suppressed in the large-ratio component for 2 of the monkeys. There was, therefore, a schedule-dependent dissociation between behavioral tolerance and the residual effects: Tolerance was greater when small ratios were arranged, whereas the residual effects were more pronounced when larger ratios were arranged.