Repeated encounters with a psychoactive drug are the hallmark of abusive use. Current treatments for human opioid abuse also incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer or experimental treatments with long-lasting partial agonist opioids (e.g.,buprenorphine) or opioid antagonists (e.g.,naltrexone). Preclinical studies of the behavioral effects of such pharmacological treatments may be useful in predicting the behavioral and subjective effects of repeated opioid use in humans. The proposed projects will use drug discrimination assays to assess how pharmacological and environmental factors modulate the development of tolerance to the discriminative stimulus and rate-altering effects of selected opioids during repeated treatment with full and partial opioid agonists. We will pay particular attention to patterns of tolerance and cross- tolerance among opioids that differ in efficacy as mu agonists. One set of experiments will examine the role of agonist efficacy in patterns of tolerance and cross-tolerance to the discriminative stimulus effects of mu opioids. We will examine tolerance to mu agonists during treatment with a range of morphine treatment doses; tolerance to the same compounds during treatment with nalbuphine, which acts as a low efficacy mu agonist in drug discrimination assays; and tolerance during treatment with a relatively high efficacy agonist. We will examine tolerance produced by a compound to itself, cross-tolerance to other compounds, and any changes in relative potency among compounds as functional of repeated treatment. A second group of experiments will assess the discriminative stimulus profiles of opioid agonists and antagonists in subjects treated chronically with selected agonists and partial agonists. A third group of experiments will continue studies of stimulus effects of opioids after termination of continuous infusions of naltrexone, in order to determine in naltrexone-induced up-regulation of opioid binding sites is accompanied by changes in the activity of low efficacy opioid agonists. A fourth group will seek to characterize the stimulus effects of compounds that have low intrinsic efficacy as mu agonists, by establishing representative compounds as discriminative stimuli and examining patterns of generalization, antagonism, and cross- tolerance. A final group of experiments will continue studies of behavioral factors that modulate development of tolerance to stimulus effects of opioids. In summary, the proposed projects will assess pharmacological and behavioral factors that modify development of tolerance to the behavioral stimulus effects of clinically important opioids. Such preclinical studies of pharmacological treatment regimens may be useful in predicting the behavioral sequelae of opioid pharmacotherapies in clinical settings.
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