L R McMahon1, C P France. 1. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
Abstract
RATIONALE: Many of the effects of benzodiazepines (BZs), barbiturates, and neuroactive steroids are mediated by the gamma-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 beta-carboline-3-carboxylate (beta-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. beta-CCM, and not flumazenil, antagonized pregnanolone, suggesting that pregnanolone increased GABA-mediated chloride flux at a non-BZ site. beta-CCM antagonized triazolam with the slope of the Schild plot for beta-CCM and triazolam (food component) conforming to unity and yielding a pA2 value of 6.44. The effects of pentobarbital were not altered by beta-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 beta-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.
RATIONALE: Many of the effects of benzodiazepines (BZs), barbiturates, and neuroactive steroids are mediated by the gamma-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 beta-carboline-3-carboxylate (beta-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 steroidpregnanolone, and the barbituratepentobarbital in that order of potency. beta-CCM, and not flumazenil, antagonized pregnanolone, suggesting that pregnanolone increased GABA-mediated chloride flux at a non-BZ site. beta-CCM antagonized triazolam with the slope of the Schild plot for beta-CCM and triazolam (food component) conforming to unity and yielding a pA2 value of 6.44. The effects of pentobarbital were not altered by beta-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 beta-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.