This research will systematically examine associative influences on tolerance to morphine's analgesic effects. Associative tolerance will be produced by pairing a distinctive context with morphine given at a long interdose interval. The experiments will evaluate the effect of blockade of N-methyl-D-Aspartate (NMDA) receptors on the development and expression of associative tolerance, determine if interoceptive effects of ethanol can serve as conditioned stimuli in the acquisition of associative tolerance, and compare effects produced with either associative or instrumental tolerance-induction procedures. This research will also test models of associative tolerance and will provide further characterizations of the extent to which associative and nonassociative tolerance processes represent different tolerance mechanisms. Furthermore, the research will yield important new information on the nature of the cues that can support associative tolerance and the contributions of associative and instrumental conditioning to learned tolerance effects. These studies will specifically: (1) examine the impact of a noncompetitive (MK-801) and a competitive NMDA receptor antagonist (LY274614) on the development of associative tolerance; (2) evaluate the impact of MK-801 and LY274614 on associative tolerance when the antagonists are co-administered with morphine both during tolerance development and tolerance testing; (3) determine if MK-801 or LY274614 reverses the expression of associative tolerance; (4) determine the conditions under which ethanol doses can acquire associative control over morphine tolerance; and (5) compare patterns of tolerance produced when animals practice the test response during tolerance acquisition with those produced through the associative tolerance paradigm. The results may have direct implications for the development of drug tolerance and dependence in addictive disorders. The data will also have relevance for the evaluation of pharmacological agents developed to block tolerance. Finally, the results will provide an evaluation of hypothetical processes subserving associative tolerance that have been posited to be functional in addictive disorders.
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