These experiments have three main goals. The first goal is to comprehensively test whether variables known to have a regulatory effect in the development and expression of associative and nonassociative tolerance to morphine's analgesic effects also are operative in the control of associative and nonassociative tolerance to nicotine's analgesic effects. The second goal is to study how differential genetic sensitivity to nicotine's effects influences the development of associative and nonassociative tolerance. The third goal is to investigate the role of nicotine-induced corticosterone release in the development of associative and nonassociative tolerance phenomena. This third question will be investigated in parallel with the first two goals. Five experiments will (1) evaluate the effect of number of conditioning trials in the development of associative tolerance to nicotine's analgesic effects, (2) examines the modulating effects of interdose interval (IDI) in the development and magnitude of associative and nonassociative nicotine tolerance, (3) establish the extent to which associative and nonassociative nicotine tolerance effects are retained in the presence versus the absence of extinction procedures, (4) attempt to obtain a nicotine dose-dependent analgesic response in rat strains that are hypothesized to be differentially sensitive to nicotine, and (5) investigate the development of tolerance to nicotine's analgesic effects across rat strains that are differentially sensitive to nicotine. Experiment 1 will include independent groups of rats to study corticosterone changes as a function of exposure to the experimental manipulations. Corticosterone measures will examine how corticosterone fluctuates as a function of nicotine delivery in the presence and absence of drug predictive cues, and as a function of a placebo challenge in the presence of drug predictive cues. If these corticosterone analyses produce meaningful results, Experiments 2, 3, and 5 will also include concurrent measurement of corticosterone levels and analgesic responses. Experiment 5 will be conducted only if Experiment 4 yields the expected results. The present application does not request funding for the corticosterone measurements and Experiment 5; funding for these elements of the investigation will be sought through a competing supplemental application.
