A comparison of fixed and variable doses of cocaine in producing and augmenting tolerance to its effects on schedule-controlled behavior.

Twelve pigeons were trained to peck a key under a fixed-ratio 20-response schedule of food presentation. Acute effects of cocaine (03-10.0 mg/kg), determined by administering the drug once per week, revealed dose-dependent decreases in frequency of key pecking. The pigeons were then divided into six pairs, matched with respect to acute dose-response curves. One of each pair received one of five different doses before each daily session (variable-dosing condition) and the other received a fixed dose equal to the arithmetic average of the doses experienced by its pair mate (fixed-dosing condition). Following 50 days of exposure, subjects in the variable-dosing condition were then switched to the fixed-dosing condition. Dose-response functions were then determined in both groups by substituting doses for the fixed daily dose, once per week. Rate-decreasing effects were attenuated similarly in both groups of subjects, both at the end of the variable-dosing regimen and during subsequent fixed dosing. Next, an attempt was made to increase the degree of tolerance. Specifically, pigeons in the variable-dosing condition were exposed repeatedly to a range of doses in which the largest dose was 1/8 to 1/4 log unit larger than in the original variable-dosing phase. Pigeons in the fixed-dosing group were exposed daily to the largest dose that did not eliminate key pecking by the end of the initial repeated-dosing regimen. Dose effects were determined after at least 35 days of exposure. If the dose-response function had shifted to the right, the largest dose for the variable-dosing subjects was increased by 1/8 to 1/4 log unit and the smallest dose in the sequence was eliminated, and another period of variable dosing commenced. For the fixed-dosing subjects, if the curve had shifted to the right, the fixed dose was increased by 1/8 to 1/4 log unit and the process repeated. Only very modest shifts of the dose-response function to the right were observed, and in several cases curves shifted left after exposure to larger doses. Overall the results suggest that a variable-dosing regimen holds promise as a technique for investigating the development of tolerance to the effects of cocaine, and that the magnitude of tolerance cannot be increased to any great degree by increasing the dose or doses repeatedly experienced. Additionally, it appears that experience with relatively large doses of cocaine may limit the degree to which tolerance can be developed, or decrease the magnitude of tolerance previously observed.