Liang Jian-Hui, Chen Feng, Krstew Elena, Cowen Michael S, Carroll Fiona Y, Crawford Duncan, Beart Philip M, Lawrence Andrew J
Department of Neuropharmacology, National Institute of Drug Dependence, University of Peking, Beijing, P.R. China.
Neuropharmacology. 2006 Apr;50(5):632-9. doi: 10.1016/j.neuropharm.2005.11.011. Epub 2006 Jan 9.
GABA systems have been implicated as targets for ethanol at the cellular, molecular and behavioural level. The present study was designed to further examine the potential of the GABA(B) receptor as a target for regulating operant alcohol responding. Given that the prototypic agonist, baclofen, reduces the self-administration of alcohol, we hypothesized that the GABA(B) receptor allosteric modulator, CGP7930, might have similar actions but a reduced side-effect profile. In this context, inbred alcohol-preferring (iP) rats were trained to respond for 10% v/v ethanol in a fixed ratio paradigm; all drug testing was performed under an FR3 schedule. Both baclofen and CGP7930 independently reduced voluntary responding for 10% ethanol in a dose-related manner. Neither drug impacted upon responding for water. A combination of subthreshold doses of baclofen and CGP7930 was also able to reduce operant responding for ethanol, suggesting that CGP7930 is indeed acting to facilitate GABA(B) receptor-mediated signalling in this paradigm. These data demonstrate the potential of positive allosteric modulators of metabotropic GABA(B) receptors to regulate alcohol responding.
γ-氨基丁酸（GABA）系统在细胞、分子和行为水平上都被认为是乙醇作用的靶点。本研究旨在进一步探究GABA（B）受体作为调节操作性酒精反应靶点的潜力。鉴于原型激动剂巴氯芬可减少酒精的自我给药，我们推测GABA（B）受体变构调节剂CGP7930可能具有类似作用，但副作用较小。在此背景下，对近交系嗜酒（iP）大鼠进行训练，使其在固定比率模式下对10% v/v乙醇做出反应；所有药物测试均在FR3程序下进行。巴氯芬和CGP7930均以剂量相关的方式独立减少了对10%乙醇的自主反应。两种药物对水的反应均无影响。阈下剂量的巴氯芬和CGP7930联合使用也能够减少对乙醇的操作性反应，这表明在该模式下CGP7930确实起到了促进GABA（B）受体介导信号传导的作用。这些数据证明了代谢型GABA（B）受体的正变构调节剂在调节酒精反应方面的潜力。
