Across nearly all licit and illicit drug classes, men are more likely than women to use, abuse and b dependent on drugs. This """"""""gender gap"""""""" may be at least partially explained by differences in psychosocial factors between women and men; however, it is not known whether individual differences in drug-taking behavior also reflect biological differences in reinforcing and subjective effects of drugs. Recent research indicates that there are significant sex differences in central dopaminergic neurobiology in rodents, which may underlie sex differences in the behavioral effects of some abused drugs - The purpose of the proposed research is to characterize (in rats) sex differences in the behavioral effects of a major class of abused drugs -- opioids. Second, two potential mechanisms underlying sex differences in behavioral effects of opioids will investigated: sex differences in opioid receptor pharmacology, and sex differences in gonadal hormones. The electrical brain stimulation procedure will be used to examine sex differences in basal reinforcement threshold, and sex differences in the reinforcing effects of opioids -- the hypothesis being that gender differences in drug taking and dependence in humans may be related to sex differences in reinforcing effects of drugs. The drug discrimination procedure will be used to examine sex differences in discriminative effects of opioids -- the hypothesis being that gender differences in drug-taking and dependence in humans may be related to se differences in subjective effects or discriminability of drugs. In addition, because analgesia is a prima therapeutic effect of opioids, and substantially contributes to their use, sex differences in antinociceptive effect of opioids also will be examined using the hotplate and tail-withdrawal assays. Preliminary data indicate that female rats have lower basal reinforcement thresholds than males in the electrical brain stimulation procedure, females discriminate a lower dose of morphine than males in the drug discrimination procedure, and female are less sensitive than males to the antinociceptive effects of morphine - Systematic investigation of the effect of a variety of mu, kappa and delta opioid agonists in each of the three procedures will be conducted in gonadally intact female and male rats. Opioid antagonist studies also will be conducted to confirm mechanism of action of the agonists, and to determine whether differences in opioid receptor pharmacology underlie sex differences behavioral effects of opioids. Finally, behavioral effects of opioids will be compared in sham-gonadectomize versus gonadectomized female and male rats, without and then with hormone replacement, to examine the role of gonadal hormones in behavioral effects of opioids.
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