Overlapping, but not identical, discriminative stimulus effects of the neuroactive steroid pregnanolone and ethanol

Many behavioral effects of neuroactive steroids are mediated by GABA_A receptors; however, other receptors might be involved. Ethanol has a complex mechanism of action, and many of the same receptors have been implicated in the effects of neuroactive steroids and ethanol. The goal of this study was to determine whether actions of neuroactive steroids and ethanol at multiple receptors result in similar discriminative stimulus effects. Rats discriminated 5.6 mg/kg of pregnanolone while responding under a fixed-ratio 20 schedule of food presentation. Pregnanolone, flunitrazepam and pentobarbital produced > 80% pregnanolone-lever responding. In contrast, neither morphine nor the negative GABA_A modulator β-CCE substituted for pregnanolone up to doses that markedly decreased response rates. Ethanol substituted only in some rats; in other rats, ethanol produced < 20% pregnanolone-lever responding up to rate-decreasing doses. Thus, substitution of positive GABA_A modulators, and not morphine or β-CCE, for pregnanolone in all rats suggests that positive modulation of GABA_A receptors is important in the discriminative stimulus effects of pregnanolone. Although pregnanolone might have actions at other receptors, in addition to actions at GABA_A receptors, substitution of ethanol for pregnanolone only in some rats suggests that the mechanisms of action of pregnanolone and ethanol overlap, but are not identical.