59 These results suggest a species difference in the neurotransmitter systems underlying the 3α,5β-THP stimulus cues. In the macaque monkey, 3α,5α-THP produces a discriminative stimulus effect that is similar to that of ethanol,

and sensitivity to these effects is dependent upon the phase of the menstrual cycle, with higher circulating progesterone in the menstrual cycle producing increased sensitivity to ethanol62 Furthermore, Inhibitors,research,lifescience,medical in male and female monkeys, 3α,5α-THP can produce stimulus effects similar to both a relatively low (1.0 g/kg) and higher (2.0 g/kg) dose of ethanol63 The common element in all three species tested (mice, rats, and monkeys) appears to be positive GABAA receptor modulation. The neurosteroid 3α,5β-THP substitution for ethanol shows wide individual differences

Inhibitors,research,lifescience,medical in rats, mice, and monkeys.59,60,62 This is an unusual finding, Autophagy inhibitor chemical structure because there is extensive training involved in establishing the discrimination, and such overtraining dampens variance across individuals. It has been speculated that the source of such individual variance in sensitivity to neurosteroids is due to the additive effect of experimenter-administered neurosteroids with circulating levels in neurosteroids that differ due to individual variations of HPA axis function.60 Inhibitors,research,lifescience,medical Monkeys also show a wide individual variation in the amount of ethanol they will self-administer, from an average of 1 to 2 drinks/day to an average of Inhibitors,research,lifescience,medical over 12 drinks/day The relationship between sensitivity to ethanollike effects of neurosteroids and propensity to self-administer ethanol has not been directly tested. However, the suggestion from data showing lower sensitivity to the discriminative stimulus effects of ethanol Inhibitors,research,lifescience,medical in the follicular phase of the menstrual cycle (when progesterone and DOC levels are low) and increased alcohol consumption in women during the follicular phase is intriguing.64 In addition, it has been documented in women who drink heavily and monkeys who

self-administer high daily doses of ethanol that their menstrual cycles are disrupted and progesterone levels are very low.65,66 It will second be of interest to first determine sensitivity to the discriminative stimulus effects of ethanol and then allow monkeys to self-administer ethanol to more directly correlate aspects of discriminative stimuli (subjective effects) with risk for heavy drinking. Neuroactive steroids mediate specific ethanol actions following acute administration in rodents Systemic administration of moderate doses (1 to 2.5 g/kg) of ethanol increases both plasma and brain levels of 3α,5α-THP and 3α,5α-THDOC.19,21,31,67,68 Ethanol-induced elevations in neuroactive steroids reach physiologically relevant concentrations that are capable of enhancing GABAergic transmission.