The purpose of this five-year proposal, part of the Integrative Neuroscience Initiative on Alcoholism (INIA) stress consortium, is to explore the relationship between stress response, alcohol drinking and neuroactive steroid levels in mouse, monkey and man. A large body of evidence in rodent models suggests that GABAergic neuroactive steroids contribute to ethanol sensitivity, tolerance, protection against dependence and reduce excessive alcohol consumption. Primates synthesize different steroid precursors and exhibit 5β -reductase activity that necessitates the development of a highly sensitive GCMS assay to measure both 3α,5α- and 3α,5β- reduced metabolites of progesterone, deoxycorticosterone and cortisol in primate plasma.
The overall hypothesis to be tested is that GABAergic neuroactive steroids are elevated in plasma following activation of the HPA axis and/or ethanol administration in ethanol naïve animals, but lost after chronic ethanol exposure. The effects of pharmacological activation of the hypothalamic pituitary adrenal axis and alcohol exposurewill be investigated to determine if there is an association between neuroactive steroid responses to HPA axis challenge and the propensity to drink alcohol.
The first aim will develop a highly sensitive GCMS assay to measure both 3α,5α- and 3α,5β- reduced metabolites of progesterone, deoxycorticosterone, androsterone and cortisol in primate plasma. The second aim will provide a service core to other INIA investigators exploring the effects of ethanol exposure on neurosteroid levels in mice (Howard Becker, Michael Miles, Robert Williams), HPA axis responses in cynomolgus (Kathy Grant) or macaque monkeys (David Friedman) and alcoholic humans that have been abstinent for one month (Bryon Adinoff). 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.