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 (3α,5α-P), pregnanolone (3α,5β-P), epiallopregnanolone (3β,5α-P), and epipregnanolone (3β,5β-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3α,5β-P HS)], and a structurally similar, adrenally derived steroid [3α-hydroxy-5- androstan-17-one (3α,5α-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 3α-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3β-hydroxysteroids and 3α,5β-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, 3α,5β-P and 3α,5α-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5β-reduced isomer (3α,5β-P), the 5α isomer of pregnanolone (3α,5α-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 3α,5β-P- and 3α,5α-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 3α,5α-P.