Discriminative stimulus effects of nicotine and chronic tolerance

Tolerance to discriminative stimulus (DS) effects of drugs, as observed by a shift of the dose-response curve to the right, has been observed with many addictive drugs (e.g. amphetamine, cocaine and morphine). Chronic administration of nicotine has been reported to produce tolerance to the locomotor depressant effects and aversive stimulus properties of nicotine; however, the DS effects of nicotine have not been examined for development of tolerance following chronic treatment. We report on experiments utilising a cumulative-dosing drug discrimination paradigm. Eight, male Sprague-Dawley rats were trained to discriminate nicotine (0.4 mg/kg s.c.) from saline under a fixed ratio (FR 10) schedule for food reinforcement. Multiple training sessions were given daily, and once criteria was met, cumulative doses of nicotine (0.025-1.2 mg/kg s.c.) were evaluated. Rats acquired the nicotine discrimination after 80 sessions. During this period, rats developed tolerance to the rate-depressing effects of nicotine after 20 nicotine-training sessions. Chronic treatments of nicotine in the rat's home cage for 7 days during suspended training failed to shift the dose-response curve for nicotine. Increasing the frequency to three daily injections also had no effect on nicotine discrimination. Furthermore, continuous infusions of nicotine (6.4 mg/kg/day) delivered via osmotic minipumps failed to shift the dose-response curve. No physical signs of withdrawal were apparent, particularly on lever responding, following removal of the minipump. These results suggest that under the conditions described, chronic tolerance to nicotine's DS does not develop readily.