Interdose interval effects on the development of contextual tolerance to nicotine's analgesic effects in rats (Rattus norvegicus).

Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms.

Associative and behavioral tolerance to the analgesic effects of nicotine in rats: tail-flick and paw-lick assays.

RATIONALE: Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine. OBJECTIVE: We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine. METHODS AND RESULTS: Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test. CONCLUSIONS: The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.

Meta-analysis of the efficacy of nicotine replacement therapy for smoking cessation: differences between men and women.

Gender differences in the efficacy of nicotine replacement therapies (NRTs) were examined in a meta-analytical review of 90 effect sizes obtained from a sample of 21 double-blind, placebo-controlled randomized studies. Although NRT was more effective for men than placebo at 3-month, 6-month, and 12-month follow-ups, the benefits of NRT for women were clearly evident only at the 3- and 6-month follow-ups. Giving NRT in conjunction with high-intensity nonpharmacological support was more important for women than men. That is, NRT and low support were efficacious for women at only short-term follow-up, and men benefited from NRT at all the follow-ups regardless of the intensity of the adjunct support. The results suggest that long-term maintenance of NRT treatment gains decrease more rapidly for women than men.