Acute and chronic effects of the neuroactive steroid pregnanolone on schedule-controlled responding in rhesus monkeys

This study used schedule-controlled responding to examine the acute and chronic effects of the neuroactive steroid and positive γ-aminobutyric acid A (GABA_A) modulator pregnanolone. Pregnanolone, the positive GABA_A modulator triazolam, the GABA_A chloride channel site antagonist pentylenetetrazol (PTZ) and the N-methyl-D-aspartate (NMDA) antagonist ketamine were administered to monkeys (n = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus shock termination (SST), before, during and after daily treatment with pregnanolone (3.2 mg/kg subcutaneously). Pregnanolone decreased responding in a dose- and time-related manner, with a duration of action of < 2h. Mutual antagonism occurred between pregnanolone and PTZ in the food component, and PTZ antagonized pregnanolone in the SST component. Daily treatment with pregnanolone increased the sensitivity to PTZ 24h but not 2h after daily pregnanolone administration, and daily pregnanolone treatment did not alter the sensitivity to pregnanolone, triazolam or ketamine. Baseline responding in the food component was decreased in some monkeys 24h after daily pregnanolone administration and in all monkeys 48h after discontinuation of daily pregnanolone treatment. These results suggest that positive GABA_A modulation is one mechanism by which pregnanolone decreases FR responding, and that dependence resulting from daily pregnanolone treatment is not necessarily accompanied by tolerance to pregnanolone. Failure of pregnanolone to confer tolerance under these conditions might suggest that neuroadaptations at the GABA_A receptor complex vary according to the site at which positive GABA_A modulation occurs.