Associative tolerance to nicotine analgesia in the rat: Tail-flick and hot-plate tests.

Abstract

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

Mecamylamine prevents tolerance but enhances whole brain [ 3 H]epibatidine binding in response to repeated nicotine administration in rats

“…For example, we and others have provided evidence that learning can play an important role in the tolerance which develops rapidly to NIC (see Caggiula et al 1995;Cepeda-Benito et al 1998), and research on other abused drugs indicates that number of drug exposures can be an important factor in dissociating mechanisms of tolerance (Cepeda-Benito and Tiffany 1992).…”

“…For example, when NIC is repeatedly given in conjunction with predictable environmental stimuli, the resulting tolerance has an important associative component; that is, its manifestation is dependent on the presence of those stimuli. Associative tolerance has been demonstrated for several effects of NIC in rats, including its antinociceptive effects (Caggiula et al 1991(Caggiula et al , 1995Cepeda-Benito et al 1998). The rapid reversibility of associative forms of tolerance, which can be accomplished by administering the drug in the absence of drug-related cues, makes it unlikely that they are dependent on longterm receptor changes in the brain (Siegel 1989;Caggiula et al 1995).…”

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

“…The finding of contextual tolerance after ten but not after 15 and 20 sessions could be interpreted as a spurious result. However, previous research has reported the presence of robust contextual tolerance on the hot plate after eight and 13 conditioning sessions (Cepeda-Benito et al 1998, 2000. For instance, CepedaBenito et al (2000) found that dose-response curve of rats receiving nicotine explicitly paired with the distinctive context was shifted significantly to the right of the doseresponse curve of rats that received nicotine explicitly unpaired with the context.…”

“…All solutions (saline and nicotine) were subcutaneously injected in the scruff of the neck (1 ml/kg of body weight). We chose the 1 mg/kg dose of nicotine according to the results of two previous studies in which we determined the doseresponse curve to nicotine in both the tail flick and the hot plate and found evidence of contextual tolerance after eight and 13 conditioning sessions (Cepeda-Benito et al 1998, 2000.…”

Acquisition and extinction of conditioned nicotine analgesic tolerance

“…Caggiula and his colleagues have shown that environmental cues mediate tolerance to its anorectic ef-f f fects , its tachycardiac effect (Epstein, Caggiula, Perkins, McKenzie, & Smith, 1991), its cortisone-elevating effect ; but see Davis, Cepeda-Benito, Harraid, & Wellman, 2005), and its analgesic effect (Caggiula et al, 1993;. Cepeda-Benito and colleagues have also found contextual control of the analgesic effect of nicotine (CepedaBenito, Davis, Reynoso, & Harraid, 2005;Cepeda-Benito, Reynoso, & Erath, 2000;Cepeda-Benito, Reynoso, & McDaniel, 1998).…”