An investigation of endogenous neuroactive steroid-induced modulation of ethanol's discriminative stimulus effects

Neuroactive steroids exhibit rapid non-genomic central nervous system activity, including modulation of GABA(A) and NMDA receptors, two receptors known to mediate the effects of methanol. Neuroactive steroids that modulate GABA(A) receptors in a manner similar to ethanol were expected to potentiate the discriminative stimulus and/or rate-suppressing effects of ethanol. In contrast, neuroactive steroids that modulate GABA(A) or NMDA receptors in a manner opposite to ethanol were hypothesized to attenuate the effects of ethanol. Adult male rats were trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) from water (i.g.). Animals were pretreated with subthreshold doses (i.p.) of ethanol and neuroactive steroids and exposed to an acute stressor (n = 5), prior to conducting ethanol cumulative-dosing (i.p.) tests. Only ethanol and 3β,5β-P pretreatments potentiated the discriminative stimulus effects of ethanol. None of the six neuroactive steroid manipulations attenuated the effects of ethanol. These results demonstrate that a neuroactive steroid, endogenous in humans, can enhance the interoceptive effects of ethanol.