The objective of this proposal is to explore the potential role of endogenous neuroactive steroids in the development of ethanol dependence. We propose to investigate whether the potent GABA/A receptor neuroactive steroid, 3alpha-hydroxy-5alpha pregnan-20-one (3alpha-5alpha-THP) prevents the development of the negative symptoms associated with ethanol withdrawal and thereby alters the development of ethanol dependence. Preliminary evidence from our lab has demonstrated that 3alpha-5alpha-THP protects against bicuculline-induced seizures in ethanol-dependent rats. 3alpha-5alpha-THP may influence the development of the negative symptoms of chronic ethanol intake which may alter the development of ethanol dependence. 3alpha-5alpha-THP is present in brain of male and female rats (107,110). The levels of 3alpha-5alpha-THP in brain during acute stress in male rats (110) and during proestrus and estrus in female rats (101) are sufficient to modulate GABA/A receptor function in brain. Epidemiological studies have shown that the men have substantially higher rates of alcohol dependence than women between the ages of 20-50 (17,50,51). Higher levels of neurosteroids in female brain may play a role in the development of alcoholism and explain why the incidence of alcoholism in women is significantly lower than men during the years of normal menstruation. The first goal of this proposal will be to determine whether chronic ethanol administration causes sensitization to the effects of 3alpha-5alpha-THP in vivo and in vitro. We propose to investigate whether 1) 3alpha-5alpha-THP alters bicuculline-induced seizure susceptibility in ethanol-dependent rats; 2) chronic ethanol administration alters 3alpha-5alpha-THP potentiation of GABA/A receptor function and binding to GABA/A recognition sites in cerebral cortex and 3) chronic ethanol administration alters endogenous 3alpha-5alpha-THP levels in blood and brain. The second goal will be to determine whether 3alpha- 5alpha-THP and ethanol co-administration alters the development of ethanol dependence. The effect of chronic co-administration of 3alpha-5alpha-THP levels in blood and brain will be measured at the termination of each experiment. These studies will test the hypotheses that chronic ethanol administration sensitizes rats to the anti-dependence. The results of this investigation will extend our knowledge of the potential role of neurosteroids in ethanol dependence and may identify new factors which are involved in the etiology of alcoholism.
