June Harry L, Foster Katrina L, McKay Peter F, Seyoum Regat, Woods James E, Harvey Scott C, Eiler William J A, Grey Collette, Carroll Michelle R, McCane Shannan, Jones Cecily M, Yin Wenyuan, Mason Dynesha, Cummings Rancia, Garcia Marin, Ma Chunrong, Sarma P V V S, Cook James M, Skolnick Phil
Psychobiology Program, Department of Psychology, Indiana University-Purdue University, Indianapolis, IN 46202, USA.
Neuropsychopharmacology. 2003 Dec;28(12):2124-37. doi: 10.1038/sj.npp.1300239.
It has been hypothesized that alcohol addiction is mediated, at least in part, by specific gamma-aminobutyric acid(A) (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 VP(A1) 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 microg) 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.
据推测，酒精成瘾至少部分是由腹侧苍白球（VP）内特定的γ-氨基丁酸A（GABA(A)）受体介导的。在调节VP内觅酒行为的潜在GABA(A)受体亚型中，GABA(A)α1受体亚型（GABA(A1)）似乎最为突出。在本研究中，我们开发了β-咔啉-3-羧酸叔丁酯（βCCt），一种混合激动剂-拮抗剂苯二氮䓬（BDZ）位点配体，它对A1受体具有结合选择性，以探索VP(A1)受体在酒精欣快特性中的功能作用。然后，在将其微量注入VP后，确定了βCCt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，双侧微量注入βCCt（0.5 - 40微克）可显著降低酒精强化行为。此外，向VP注入βCCt表现出神经解剖学和强化物特异性。因此，在伏隔核（NACC）/尾状壳核（CPu）注入后未观察到对酒精强化行为的影响，对糖精维持的反应也无影响。肠胃外给药的βCCt（1 - 40毫克/千克）在降低P和HAD-1大鼠的酒精强化行为方面同样有效且具有选择性。对运动活性的额外测试表明，βCCt可逆转氯氮卓（10毫克/千克）和乙醇（1.25克/千克）产生的运动性镇静作用，但单独给药时无内在作用。在非洲爪蟾卵母细胞中表达的重组受体上进行的研究表明，βCCt在α3β3γ2和α4β3γ2受体上作为低效部分激动剂起作用，在α1β3γ2、α2β3γ2和α5β3γ2受体上作为低效反向激动剂起作用。本研究表明，βCCt能够拮抗酒精的强化和镇静特性。βCCt的这些抗酒精特性主要通过GABA(A1)受体介导。βCCt可能代表一种药物治疗剂的原型，可有效减少人类酗酒者的饮酒行为。
