Role of dose order in the development of tolerance to effects of cocaine on schedule-controlled behavior in pigeons

Abstract

Rationale. Tolerance to behavioral effects of cocaine can be produced by exposure to varying doses. The degree to which tolerance develops may depend on dose order.

Objective. To investigate the relationships between three sequences of doses of cocaine in a daily, variable-dosing regimen and the development of tolerance to effects on schedule-controlled behavior.

Methods. Twelve pigeons responded daily under a fixed-ratio 20 schedule of reinforcement, and performance was investigated under a range of doses of cocaine (0.3–10.0 mg/kg, i.m.) by administering the drug once every 7 days (acute effects). After determination of acute effects of cocaine, the drug was administered daily with dose varying from day to day. Dose order varied systematically across three groups of four pigeons; doses were delivered in ascending, descending, or "sawtooth" (ascending then descending) sequences. This variable-dosing regimen continued until drug effects were stable (at least 13 cycles through all doses).

Results. During the acute-dosing regimen, response rates following small cocaine doses were similar to those under control conditions; following moderate-to-high doses, responding was diminished relative to control rates. During the variable-dosing regimen, tolerance to the rate-decreasing effects of cocaine was observed in all groups, regardless of the order in which the drug was delivered, and the magnitude of tolerance was similar across groups. Systematic differences in the rate of recovery from initial response decrements were observed across groups, with rate of recovery fastest under the ascending sequence.

Conclusions. These results suggest that dose order under a variable-dosing regimen does not significantly affect the final attainment of tolerance, although it may contribute to the speed with which tolerance develops.