The primary aim of this RSDA application is to release Dr. Young from the majority of her undergraduate teaching and administrative responsibilities so that she can devote increased time and effort to drug abuse research and research training. Specifically, she will devote the majority of her time to projects supported by DA03796 (Behavioral pharmacology of opioid tolerance). These projects use drug discrimination assays to assess how pharmacological and behavioral factors modulate the development of tolerance to the discriminative effects of mu opioids, with particular attention to patterns of tolerance and cross-tolerance among opioids that differ in relative intrinsic efficacy. The first project will examine the role of agonist efficacy in patterns of tolerance and cross-tolerance to the morphine-like discriminative stimulus effects of mu opioids. Experiments will examine tolerance to mu agonists during treatment with several doses of morphine, tolerance to the same compounds during treatment with the low efficacy mu agonist nalbuphine, and tolerance during treatment with the high efficacy agonist fentanyl. Tests will examine tolerance produced by a compound to itself, cross-tolerance to other compounds, and any changes in relative potency among compounds as function of repeated treatment. A second project will examine the stimulus effects of opioids in opioid- dependent subjects. A third project will conduct studies with irreversible opioid receptor antagonists, in order to provide an independent test of the hypothesis that differences in tolerance are related to differences in agonist intrinsic efficacy. A fourth project will study the stimulus effects of low efficacy agonists per se, by establishing representative compounds as discriminative stimuli and examining patterns of generalization and cross-tolerance. A final project will examine whether up-regulation of opioid binding sites is followed by differential changes in the stimulus effects of lower and higher efficacy agonists. Dr. Young will also devote time to projects evaluating the pharmacological and behavioral influences of prototypic competitive and non-competitive NMDA antagonists on the development of tolerance to the antinociceptive and discriminative stimulus effects of morphine (MH47181), and to research training supported by MARC (GM08030 and MH17153) and MBRS (RR08167) training grants. These latter grants provide intensive research training for undergraduate and graduate minority students, who participate in the projects described above.
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