80 A strong correlation exists between plasma and brain levels of DOC. The temporal and regional associations found in these studies suggest that the steroids originate in the adrenals and are transported to the brain. Upon entering the brain the steroids are metabolized by 5α-reductase and 3α-dehydrogenase enzymes. These enzymes display

brain region and cell specific expression81 that may be responsible for the regional distribution of steroid levels following acute ethanol administration. Furthermore, DOC levels measured in the Khisti et al study Inhibitors,research,lifescience,medical are comparable to 3α,5αselleck products -THDOC levels measured in plasma and brain,21 suggesting that DOC formed after acute ethanol administration may be largely converted to the GABAergic neurosteroid 3α,5α-THDOC. Studies of ethanoPs effects on neurosteroid precursors are important not only to determine the sources and Inhibitors,research,lifescience,medical synthesis of potent metabolites, but

also to establish their role in physiological functions. Effects of neuroactive steroids on drinking behavior in rodents The GABAergic system is important in regulating ethanol consumption, and neurosteroids can also alter drinking behavior through their actions on GABAA receptors. 3α,5α-THP Inhibitors,research,lifescience,medical dose-dependently increased ethanol self-administration in nondependent ethanolpref erring P rats, while decreasing ethanol administration in ethanol-dependent P rats.4 This suggests a complex relationship whereby neurosteroids may promote drinking in nondependent animals consuming small amounts of ethanol, while protecting against excessive drinking in dependent animals. This Inhibitors,research,lifescience,medical possibility is supported by data in

male C57BL/6J mice where 3α,5α-THP dose-dependently Inhibitors,research,lifescience,medical modulated ethanol intake in a 2-hour session, with low doses (3.2 mg/kg) increasing ethanol consumption and high doses (24 mg/kg) decreasing ethanol consumption.82 In addition, at doses of 10 and 17 mg/kg, 3α,5αTHP has been shown to have rewarding properties in mice.83 However, other studies in nondependent rats have shown that pretreatment with a 3 mg/kg dose aminophylline of 3α,5αTHP, but not a 1- or 10-mg/kg dose, increases oral selfadministration of ethanol84 This result suggests that 3α,5α-THP dose-dependently mediates some of the reinforcing effects of ethanol, and its concentration in brain may have an important influence on drinking behavior. Indeed, Sardinian alcohol-preferring rats have larger 3α,5α-THP and 3α,5α-THDOC elevations after ethanol administration than their non-alcohol-preferring counterparts.21 Other studies have shown that increased ethanol intake after 3α,5α-THP administration is selective for ethanol-reinforced responding, and cannot be attributed to palatability or increased motor activity during the experimental sessions.