The general objectives of the proposed research are to compare the tolerance that develops to the analgesic effects of morphine when drug administration is paired reliably with distinctive cues (""""""""associative tolerance"""""""") to the tolerance that develops when drug administration is systematically unpaired with such cues (""""""""nonassociative tolerance""""""""). The studies in this proposal will evaluate factors controlling the development of associative and nonassociative forms of morphine tolerance, examine potential interactions between these two forms of morphine tolerance, examine potential interactions between these two forms of tolerance, explore the extent to which certain features of nonassociative tolerance can also be demonstrated in associative tolerance to morphine's analgesic effects. Furthermore, these studies will test predictions of the habituation model of drug tolerance that hypothesize that associative forms of tolerance will be retained for administration procedures promoting the development of nonassociative tolerance will disrupt the formation of associative tolerance. The studies are designed specifically to: (1) determine the magnitude of tolerance that develops when high doses of short or long interdose interval; (2) investigate the retention of morphine tolerance intervals; (3) examine the time course of the development of associative tolerance to a moderate dose of morphine; (4) determine whether a low dose of morphine can acquire and (5) determine whether behaviorally manifest compensatory responses subserve associative tolerance to morphine's analgesic effects. The results of these studies may have direct implications for the development of drug tolerance and dependence in drug abusers. The data will also have relevance for the application of various theories of drug conditioning to the clinical use of opiates, particularly with regard to the conditions that may facilitate or retard the development of tolerance. Finally, the results of these studies will provide an evaluation of hypothetical processes subserving associative tolerance that have been posited to be functional in the development and maintenance of addictive behavior.
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