Relations between dose magnitude, subject sensitivity, and the development of tolerance to cocaine-induced behavioral disruptions in pigeons.

Keypecking by 12 pigeons, maintained by a fixed-ratio 30 schedule of food presentation, was decreased in rate by acute pre-session injections of cocaine in a dose-dependent manner, with larger doses producing more disruption. A constant dose of cocaine was then injected prior to every session for 40 days. Some subjects received a relatively small dose, some received a medium-sized dose, and others received a large dose. Subsequently, dose-effects were reassessed via once-weekly probe injections, with every other session continuing to be preceded by injection of the daily dose of cocaine. Then a different dose of cocaine was administered daily for 40 more days, after which the dose-effect function was redetermined in like manner. In general, tolerance to cocaine-induced response-rate reductions was most likely to develop when (a) the repeatedly-administered dose of cocaine was relatively small (even without acute effect on keypecking) and (b) the subject's keypecking was disrupted by smaller doses of cocaine in the initial dose-effect assessment. Tolerance was generally observed as a shift in the dose-effect function that, in several cases, could be eliminated by increasing the magnitude of the daily administered dose. In addition, every subject's rate of keypecking following saline injections was lowered after daily exposure to cocaine. These results (a) are partially consistent with the reinforcement-loss account of tolerance to cocaine-induced behavioral disruptions, and (b) support previous observations of withdrawal symptoms following cessation of extended exposure to cocaine.