McMahon L R, France C P
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
Psychopharmacology (Berl). 2001 Nov;158(3):289-96. doi: 10.1007/s002130100864.
Many of the effects of benzodiazepines (BZs), barbiturates, and neuroactive steroids are mediated by the gamma-aminobutyric acid (GABA)(A) receptor complex.
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.
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.
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.
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.
苯二氮䓬类（BZs）、巴比妥类和神经活性甾体的许多作用是由γ-氨基丁酸（GABA）（A）受体复合物介导的。
本研究检验了以下假设，即负性GABA（A）调节剂可减弱不同正性GABA（A）调节剂的行为效应，这些正性GABA（A）调节剂在受体复合物上的作用位点各不相同。
恒河猴在食物呈现和刺激-电击终止的多重固定比率（FR:FR）时间表下做出反应，并在累积给药程序中接受GABA（A）调节剂。
BZ位点负性GABA（A）调节剂β-咔啉-3-羧酸甲酯（β-CCM），而非BZ位点中性调节剂氟马西尼，在多重时间表下降低了FR反应。FR反应也被正性调节剂降低，包括BZ三唑仑、神经活性甾体孕烷醇酮和巴比妥类戊巴比妥，其效力顺序依次为上述顺序。β-CCM而非氟马西尼拮抗孕烷醇酮，表明孕烷醇酮在非BZ位点增加了GABA介导的氯离子通量。β-CCM拮抗三唑仑，β-CCM和三唑仑（食物成分）的Schild图斜率符合单位值，pA2值为6.44。β-CCM未改变戊巴比妥的作用，表明巴比妥类可能作用于与神经活性甾体和BZs作用的GABA（A）受体群体不同的群体，或者巴比妥类位点正性GABA（A）调节剂不易被负性调节剂调节。
这些结果证实了β-CCM和三唑仑之间的竞争性相互作用，并进一步证明神经活性甾体对FR反应的作用被BZ位点负性GABA（A）调节剂减弱。负性GABA（A）调节剂可能对表征通过受体复合物上不同位点起作用的正性GABA（A）调节剂之间的重要差异特别有用。
