This is a competing renewal application for a NIDA Clinical Research Center (P-50) entitled Polydrug Abuse In Women. This Center focuses on the neurobiology of drug abuse in women and the role of neuroendocrine hormones in modulating the determinants and consequences of chronic drug dependence. Recent evidence of significant gender differences in response to therapeutic medications as well as in vulnerability to drug-related cerebrovascular, endocrine and immune disorders indicates the importance of studying the interactions between drugs of abuse and neuroendocrine function. The adverse health impact of drug abuse is poignantly illustrated by the fact that over 50 percent of AIDS cases in women involve i.v. drug abuse and needle sharing. and that AIDS is now the sixth leading cause of death among American women. Polydrug abuse and cocaine dependence are also associated with life-threatening cardiovascular and cerebrovascular disorders, abnormalities of reproductive function and compromised fetal development. We propose five related studies to compare the behavioral and biological determinants and consequences of cocaine and polydrug abuse in women and men as well as in established primate models of reproductive biology and drug self-administration. The influence of menstrual cycle phase on cocaine's behavioral and endocrine effects and pharmacokinetics will be examined in women. Gender comparisons should clarify the role of neuroendocrine hormones in affecting these cocaine-related endpoint measures. Cocaine's effects on gonadal steroid hormones will be examined in males and females, and the interactions with anterior pituitary hormones will be studied in ovariectomized females during various regimens of gonadal steroid replacement. The effects of chronic cocaine self-administration and withdrawal on disruptions of prolactin regulation (e.g., hyperprolactinemia) will be compared in males and females using a dopamine perturbation model. The possible mechanisms underlying prolactin disregulation will be examined with specific receptor antagonists. Modulation of pain sensitivity and opioid analgesia by ovarian steroids and neuroactive steroids will be examined in a well validated model of acute thermal algesia and hyperalgesia. Analgesic efficacy will be measured across phases of the menstrual cycle and in ovariectomized females under ovarian steroid replacement conditions that mimic four phases of the menstrual cycle as well as late pregnancy. The endocrine consequences of acute and chronic treatment with buprenorphine, a new drug abuse treatment medication, will be studied in an established primate model of reproductive biology. Buprenorphine's relative reproductive toxicity will be evaluated under controlled conditions where polydrug abuse cannot confound interpretation of data obtained. The effectiveness of potential treatment medications in reducing drug self-administration also will be examined. Mu, delta and kappa receptor selective opioids, dopamine receptor antagonists and dopamine reuptake inhibitors will be studied in cocaine, heroin and speedball self-administration and drug discrimination paradigms in both males and females.
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