GABA A modulators acting at benzodiazepine or neuroactive steroid binding sites have qualitatively similar but quantitatively different effects in monkeys discriminating either pregnanolone or midazolam

In general, positive γ‐aminobutyric acid A (GABA A ) modulators, including benzodiazepines and neuroactive steroids, produce qualitatively similar behavioral effects; however, differences emerge during chronic treatment with tolerance often developing to benzodiazepines and not to neuroactive steroids. The current study further compared GABA A modulators in separate groups of rhesus monkeys discriminating either 5.6 mg/kg of the neuroactive steroid pregnanolone or 0.178 mg/kg of the benzodiazepine midazolam. Positive GABA A modulators produced drug‐lever responding in both groups; however, pregnanolone was 3‐fold more potent and midazolam was 3‐fold less potent in monkeys discriminating pregnanolone. Although flumazenil dose dependently antagonized the effects of midazolam and enhanced the effects of pregnanolone, larger doses of flumazenil were needed to obtain these effects in monkeys discriminating pregnanolone. Increased sensitivity to neuroactive steroids and decreased sensitivity to benzodiazepines in monkeys discriminating pregnanolone indicate that GABA A modulators are not acting identically in these groups. Thus, there appears to be some variation in the mechanism of action of each positive GABA A modulator across these two experimental conditions. Supported by USPHS grants DA09157 and DA017918.