The reinforcing properties of alcohol are mediated by GABAA1 receptors in the ventral pallidum
The reinforcing properties of alcohol are mediated by GABAA1 receptors in the ventral pallidum
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DOI：
10.1038/sj.npp.1300239
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发表时间：
2003-12-01
影响因子：
7.6
通讯作者：
Skolnick, P
中科院分区：
文献类型：
--
作者：
June, HL;Foster, KL;Skolnick, P
已有假说认为酒精成瘾至少部分是由腹侧苍白球(VP)内特定的GABA(A)受体介导的。在调节VP内酒精寻求行为的潜在的GABA(A)受体亚型中，GABA(A)α1受体亚型(GABA(A1))尤为突出。在本研究中，我们开发了一种在A1受体上具有结合选择性的混合激动剂-拮抗剂苯二氮卓(BDZ)位点配体-β-Caroline-3-羧酸叔丁酯(BetaCCt)，以探讨VPA1受体在酒精兴奋特性中的功能作用。然后向VP微量注射BetaCCt的体内作用，VP是一种主要表达A1受体的新型酒精奖赏底物。在两种选择性培育的慢性饮酒啮齿动物模型(HAD-1，P大鼠)中，双侧微量注射BetaCCt(0.5-40杯)可显著减少酒精强化行为。此外，VP输注BetaCCt表现出神经解剖学和增强剂的特异性。因此，在伏隔核(NACC)/尾壳核(CPU)内注射酒精对酒精增强的行为没有影响，也没有对糖精维持的反应产生影响。胃肠外注射BetaCCT(1-40 mg/kg)对减少P和HAD-1大鼠的酒精强化行为具有同等的有效性和选择性。额外的运动活动测试显示，倍他乐克逆转了氯氮卓酮(10 mg/kg)和乙醇(1.25 g/kg)所产生的运动镇静，但单独给药时没有内在作用。在非洲爪哇卵母细胞中表达的重组受体的研究表明，BetaCCt在α3β3 Gamma2和α4β3 Gamma2受体上作为低效部分激动剂，在α1β3 Gamma2、α2β3 Gamma2和α5β3 Gamma2受体上作为低效反向激动剂。本研究表明，倍他乐克可拮抗酒精的增强作用和镇静作用。BetaCCt的这些抗酒精特性主要是通过GABA(A1)受体介导的。BetaCCt可能代表了一种药物治疗剂的原型，可以有效地减少人类酗酒者的饮酒行为。
It has been hypothesized that alcohol addiction is mediated, at least in part, by specific gamma-aminobutyric acidA (GABA(A)) receptors within the ventral pallidum (VP). Among the potential GABA(A) receptor isoforms regulating alcohol- seeking behaviors within the VP, the GABA(A) alpha1 receptor subtype (GABA(A1)) appears pre-eminent. In the present study, we developed beta-carboline-3-carboxylate-t-butyl ester (betaCCt), a mixed agonist-antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VPA1 receptors in the euphoric properties of alcohol. The in vivo actions of betaCCt were then determined following microinfusion into the VP, a novel alcohol reward substrate that primarily expresses the A1 receptor. In two selectively bred rodent models of chronic alcohol drinking (HAD-1, P rats), bilateral microinfusion of betaCCt (0.5 - 40 mug) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of betaCCt exhibited both neuroanatomical and reinforcer specificity. Thus, no effects on alcohol- reinforced behaviors were observed following infusion in the nucleus accumbens (NACC)/ caudate putamen (CPu), or on response maintained by saccharin. Parenteral-administered betaCCt (1 - 40 mg/kg) was equally effective and selective in reducing alcohol-reinforced behaviors in P and HAD-1 rats. Additional tests of locomotor activity revealed that betaCCt reversed the locomotor sedation produced by both chlordiazepoxide ( 10 mg/kg) and EtOH ( 1.25 g/kg), but was devoid of intrinsic effects when given alone. Studies in recombinant receptors expressed in Xenopus oocytes revealed that betaCCt acted as a low-efficacy partial agonist at alpha3beta3gamma2 and alpha4beta3gamma2 receptors and as a low-efficacy inverse agonist at alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors. The present study indicates that betaCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of betaCCt are primarily mediated via the GABA(A1) receptor. betaCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics.