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.

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Previous assessments of associative nicotine tolerance may have confounded associative effects with novelty-induced stress effects, instrumental learning effects, or both. That is, subjects were tested in novel environments, allowed to practice the test response, or both during the tolerance development phase. In the first study, 32 male Sprague-Dawley rats were injected with various doses of nicotine and tested for nociception in the tail-flick and hot-plate tests to assess nicotine's analgesic effects. In the second study, 35 rats received nicotine explicitly paired or unpaired with a distinctive test context. All animals were equally preexposed to the test environment, and none had the opportunity to practice the test response. Paired rats developed greater nicotine tolerance than unpaired rats. This context-dependent (associative) tolerance effect was found with both tail-flick and hot-plate tests.Drug tolerance is a decrease in the effects of a drug dose following repeated drug administrations. Drug tolerance is central to the definition of drug dependence (American Psychiatric Association, 1994), and several theorists assign tolerance, or the mechanisms that produce tolerance, an important role in the genesis and maintenance of addictive behaviors (see Ramsay & Woods, 1997;Trujillo & Akil. 1995). For example, smokers may smoke more to compensate for the development of tolerance of the reinforcing effects of nicotine. Likewise, tolerance of the ill effects of nicotine may increase tobacco consumption by allowing smokers to smoke more without feeling sick (Alexander & Hadaway, 1982;Pomerleau, 1995;Trujillo & Akil). Thus, nicotine tolerance can be a symptom of physical dependence on nicotine (American Psychiatric Association, 1994) and a contributor to the severity of the smoker's physical and psychological dependence (Pomerleau).There is considerable evidence that many examples of drug tolerance represent the operation of classical conditioning (Young & Goudie, 1994), and some theorists have proposed that "learning is the primary underlying cause" (Ramsay & Woods, 1997, p. 170) of all drug tolerance phenomena. Most of the support for the role of classical conditioning in the development of drug tolerance comes from investigations of tolerance to the analgesic effects of morphine. In associative tolerance studies, animals receiving morphine explicitly paired with a distinctive test context

This study is the first to demonstrate associative tolerance to nicotine's analgesic effects as a shift in the dose-response curve (DRC) to the right. The subjects were 43 experimentally naive, male Sprague Dawley rats (Rattus norvegicus) randomly assigned to 2 groups. Home cage rats (HC; n = 21) received a series of 1 mg/kg nicotine doses explicitly unpaired with the distinctive context, whereas distinctive context rats (DC; n = 22) were injected with nicotine explicitly paired with the distinctive context. Rats in each of the 2 groups were randomly assigned to 1 of 3 nicotine testing doses to construct DRCs. The DRC of the rats that received nicotine in the distinctive context was shifted to the right of the DRC of rats that had had as much exposure to nicotine but had never experienced nicotine in the distinctive context. DC rats required nearly twice as much nicotine as HC rats to produce the same DRC. The discussion describes the implications of the results for theories of drug tolerance and nicotine addiction.