The negative GABA_A modulator methyl β-carboline-3-carboxylate attenuates the behavioral effects of the positive GABA_A modulators triazolam and pregnanolone in rhesus monkeys

Rationale: Many of the effects of benzodiazepines (BZs), barbiturates, and neuroactive steroids are mediated by the γ-aminobutyric acid (GABA)_A receptor complex. Objectives: This study tested the hypothesis that negative GABA_A modulators attenuate the behavioral effects of different positive GABA_A modulators that vary in their site of action on the receptor complex. Methods: Rhesus monkeys responding under a multiple fixed ratio (FR:FR) schedule of food presentation and stimulus-shock termination received GABA_A modulators under cumulative dosing procedures. Results: The BZ site negative GABA_A modulator methyl β-carboline-3- carboxylate (β-CCM), and not the BZ site neutral modulator flumazenil, decreased FR responding under the multiple schedule. FR responding was also decreased by positive modulators, including the BZ triazolam, the neuroactive steroid pregnanolone, and the barbiturate pentobarbital in that order of potency. β-CCM, and not flumazenil, antagonized pregnanolone, suggesting that pregnanolone increased GABA-mediated chloride flux at a non-BZ site. β-CCM antagonized triazolam with the slope of the Schild plot for β-CCM and triazolam (food component) conforming to unity and yielding a pA₂ value of 6.44. The effects of pentobarbital were not altered by β-CCM, suggesting that barbiturates might act at a population of GABA_A receptors different from those where neuroactive steroids and BZs act, or that barbiturate site positive GABA_A modulators are not amenable to modulation by negative modulators. Conclusions: These results confirm a competitive interaction between β-CCM and triazolam, and further demonstrate that the effects of neuroactive steroids on FR responding are attenuated by a BZ site negative GABA_A modulator. Negative GABA_A modulators might prove especially useful for characterizing important differences among positive GABA_A modulators that act through different sites on the receptor complex.