Ethanol-like discriminative stimulus effects of endogenous neuroactive steroids: Effect of ethanol training dose and dosing procedure

A number of endogenous steroids exhibit rapid, nongenomic effects on the ce ntral nervous system and are called neuroactive steroids. The rapid mechani sms of action include modulation of gamma-aminobutyric acid type A (GABA(A) ) and N-methyl-D-aspartate (NMDA) receptors, which are two receptors implic ated in the behavioral effects of ethanol. It was hypothesized that neuroac tive steroids that positively modulate GABA(A) receptors or negatively modu late NMDA receptors, analogous to the actions of ethanol, would produce dis criminative stimulus effects similar to ethanol. Two groups of male Long-Ev ans rats (n = 6-8/group) were trained to discriminate between 1.0 or 2.0 g/ kg ethanol (i.g.) and water (i.g.). The neuroactive steroids allopregnanolo ne, pregnanolone, epipregnanolone, allotetrahydrodeoxycorticosterone, pregn anolone sulfate, epipregnanolone sulfate, dehydroepiandrosterone, dehydroep iandrosterone sulfate, pregnenolone, and pregnenolone sulfate (PS), all adm inistered i.p., were tested for substitution with acute and cumulative dosi ng procedures (n = 4-8/steroid). The GABA(A)-positive modulatory steroids a llopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone substi tuted for ethanol, as did the low-efficacy steroid 3 beta,5 beta-P. GABA(A) -negative modulators, such as dehydroepiandrosterone sulfate and PS, and al l of the NMDA modulators tested, including PS, pregnanolone sulfate, and ep ipregnanolone sulfate, did not substitute for ethanol. These results show t hat certain endogenously occurring neuroactive steroids produce discriminat ive stimulus effects similar to those of ethanol.