Interestingly, ethanol-dependent rats develop tolerance to ethanolinduced increases in neurosteroid levels,4,79 which may influence the excessive drinking that is observed in ethanol-dependent rats.86 Together, these data suggest a strong relationship between neurosteroid levels and ethanol consumption that may involve both genetic and environmental factors. Mechanisms of ethanol-induced elevations of neuroactive steroids in plasma Inhibitors,research,lifescience,medical and brain Ethanol-induced elevations in neuroactive steroids appear to involve activation of the HPA axis to increase circulating levels of neuroactive steroids and their precursors, as well as direct effects of ethanol on brain synthesis. Adrenalectomy

completely blocks the effects of ethanol on cerebral cortical 3α,5α-THP concentrations; however, the effect of ethanol on cerebral cortical levels of 3α,5α-THP can be restored by administration of its precursor, Inhibitors,research,lifescience,medical 5α-dihydroprogester one (5α-DHP),to adrenalectomized rats.30 Since the steroid biosynthetic enzymes are present across brain,87 it is likely that ethanol-induced increases in brain levels of neuroactive steroids involve brain synthesis

that may contribute to effects of ethanol. The first step in steroid synthesis is the translocation of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where P450scc converts it to pregnenolone. Inhibitors,research,lifescience,medical This step is mediated

by steroidogenic acute regulatory protein (StAR) and/or the peripheral Inhibitors,research,lifescience,medical benzodiazepine receptor. Ethanol rapidly increases the synthesis and translocation of StAR protein from the cytosol to the mitochondria in the adrenal gland.30 Hence, it is likely that increases in GABAergic neuroactive steroids in adrenals are secondary to ethanol-induced increases in all steroid synthesis initiated by StAR activity. To determine if ethanol could alter other steroidogenic Inhibitors,research,lifescience,medical enzyme activity in rat brain and adrenal minces, Morrow and colleagues investigated the effects of ethanol on 5αreductase and 3α-hydroxysteroid dehydrogenase (3αHSD) enzyme activity (unpublished data). Ethanol (10 to 100 mM) did not alter 5α-reductase activity, measured by the conversion of [14C]progesterone to [14C]5α-DHP in tissue minces. In contrast, ethanol (30 to 100 mM) increased the conversion of [14C]5α-DHP to [14C]3α,5α-THP why by a maximum of 30 ± 3.6% in the olfactory bulb and tubercle, but had no effect in the adrenal gland. Ethanol did not alter nicotinamide adenine dinucleotide PARP activity phosphate (NADPH) effects on enzyme activity. Fluoxetine was tested as a positive control since previous studies showed that fluoxetine decreased the Km of a recombinant 3aHSD enzyme.88 Fluoxetine increased the activity of 3α-HSD enzyme in the olfactory bulb and tubercle and adrenal gland and this effect was blocked by the 3α-HSD inhibitor indomethacin.