Effects of benzodiazepine receptor ligands and ethanol in rats trained to discriminate pregnanolone

Abstract

Although GABA(A) receptor positive modulators share many behavioral effects, subtle differences have been detected among their discriminative stimulus effects. The purpose of the present study was to determine the extent of shared discriminative stimulus effects of pregnanolone with various benzodiazepine receptor ligands and with ethanol. Naive male Sprague-Dawley rats were trained to discriminate the endogenous neuroactive steroid pregnanolone (5.6 or 8.0 mg/kg) from vehicle. The benzodiazepine receptor agonists, triazolam and lorazepam, the benzodiazepine receptor partial agonist, bretazenil, the benzodiazepine1 (BZ1) receptor subtype selective agonists, zolpidem and zaleplon and ethanol were tested. Triazolam, lorazepam and bretazenil substituted for pregnanolone. Lorazepam, but not triazolam or bretazenil, decreased response rates at the highest dose tested. Zaleplon completely substituted for pregnanolone with no effect on response rates. Zolpidem substituted for pregnanolone only at a dose that severely disrupted response rates. Ethanol partially substituted for pregnanolone and decreased response rates. The results are consistent with GABA(A) receptor mediation of the discriminative stimulus effects of pregnanolone. The effects on response rates suggest subtle differentiation among the GABA(A) receptor-mediated cues.