Stress, alcohol and GABAergic neuroactive steroids in primates

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DESCRIPTION (provided by applicant): The purpose of this proposal is to explore the relationship between stress response, alcohol drinking and neuroactive steroid levels in primate plasma. A large body of evidence in rodent models suggests that GABAergic neuroactive steroids contribute to ethanol sensitivity, tolerance, protection against dependence and reduces excessive alcohol consumption. Primates synthesize different steroid precursors and exhibit 5preductase activity that necessitates the development of a highly sensitive GCMS assay to measure both 3<x5ccand 3a5p- reduced metabolites of progesterone, deoxycorticosterone and cortisol in primate plasma. The overall hypothesis to be tested is that GABAergic neuroactive steroids are elevated in primate plasma following activation of the HPA axis and/or ethanol administration in ethanol nai've monkeys, but lost after chronic ethanol exposure. The effects of pharmacological activation of the hypothalamic pituitary adrenal axis, alcohol infusion, induction of alcohol drinking and chronic alcohol consumption will be investigated to determine if there is an association between neuroactive steroid responses to HPA axis challenge and the propensity to drink alcohol. These studies will be integrated into the INIA consortium by comparison with similar studies in mice and man. The first aim will develop a highly sensitive GCMS assay to measure both 3a5a- and 3a5[3- reduced metabolites of progesterone, deoxycorticosterone and cortisol in primate plasma. The second aim will determine if HPA axis stimulation at the level of the hypothalamus (naloxone administration), pituitary (oCRF infusion) or adrenal gland (ACTH infusion after dexamethasone pretreatment) and systemic ethanol administration alters the levels of GAB A receptor neuroactive steroids in plasma of monkeys. The third aim will investigate the effect of schedule-induced drinking and ad lib ethanol consumption for one year on both the precursor steroids and neuroactive steroid levels following HPA axis stimulation using the same challenge procedure. The fourth aim will provide a service core to other INIA investigators exploring the effects of chronic ethanol exposure on neurosteroid levels in mice, macaque monkeys and alcoholic humans. Each investigator will explore if neuroactive steroid responses to ethanol or HPA axis stimulation are altered by chronic ethanol history or predictive of voluntary alcohol consumption levels.