Neuroactive Steroid Stereospecificity Of Ethanol-Like Discriminative Stimulus Effects In Monkeys

Positive modulation of GABA(A) and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione ( progesterone) [allopregnanolone (3 alpha,5 alpha-P), pregnanolone (3 alpha,5 beta-P), epiallopregnanolone (3 beta,5 alpha-P), and epipregnanolone (3 beta,5 beta-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3 alpha,5 beta-P HS)], and a structurally similar, adrenally derived steroid [3 alpha-hydroxy-5-androstan-17-one (3 alpha,5 alpha-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3 alpha-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3 beta-hydroxysteroids and 3 alpha,5 beta-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3 alpha,5 beta-P and 3 alpha,5 alpha-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5 beta-reduced isomer (3 alpha,5 beta-P), the 5 alpha isomer of pregnanolone (3 alpha,5 alpha-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3 alpha, 5 beta-P- and 3 alpha,5 alpha-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3 alpha,5 alpha-P.