Moore Catherine F, Lycas Matthew D, Bond Colin W, Johnson Bankole A, Lynch Wendy J
Department of Psychiatry and Neurobehavioral Sciences.
Exp Clin Psychopharmacol. 2014 Feb;22(1):35-42. doi: 10.1037/a0035215.
Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of consumption and relapse that acute treatment with a combination of these medications was more efficacious than either alone. To determine whether the mechanism for its beneficial effects is through modulation of ethanol's reinforcing effects, we measured the effect of this combination in male alcohol preferring (P) rats (N = 22) responding for ethanol under a progressive-ratio (PR) schedule. Low doses, which either do not affect (ondansetron; 0.001 mg/kg) or only modestly affect (topiramate; 10 mg/kg) alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side effects. In addition to acute treatment (1 day), the effects of chronic administration (10 days) were examined in an attempt to model human treatment approaches. The effects of the combination were compared with the low dose of topiramate alone hypothesizing that the combination would be more efficacious than topiramate alone. Although both topiramate and the combination similarly reduced PR responding for ethanol following acute treatment and during the initial phase of chronic treatment (Days 1-5), after repeated administration (Days 6-10), only the combination produced a sustained reduction in ethanol-maintained responding. These results suggest an advantage of the combination over topiramate alone at producing a sustained reduction in ethanol's reinforcing effects following prolonged treatment, and lend further support for its use as a potential treatment for AUDs.
托吡酯（一种γ-氨基丁酸/谷氨酸调节剂）和昂丹司琼（一种5-羟色胺-3拮抗剂）已显示出有望用于治疗酒精使用障碍（AUDs），尽管这两种药物的疗效均一般/存在差异。我们最近在饮酒和复饮的动物模型中表明，这两种药物联合急性治疗比单独使用任一药物更有效。为了确定其有益作用的机制是否是通过调节乙醇的强化作用，我们在按累进比率（PR）程序对乙醇作出反应的雄性嗜酒（P）大鼠（N = 22）中测量了这种联合用药的效果。选择单独使用时对酒精相关行为无影响（昂丹司琼；0.001 mg/kg）或仅有轻微影响（托吡酯；10 mg/kg）的低剂量，以在将潜在副作用降至最低的同时使它们的联合疗效最大化。除了急性治疗（1天）外，还研究了慢性给药（10天）的效果，以尝试模拟人类治疗方法。将联合用药的效果与单独使用低剂量托吡酯进行比较，假设联合用药比单独使用托吡酯更有效。尽管托吡酯和联合用药在急性治疗后以及慢性治疗的初始阶段（第1 - 5天）均同样降低了对乙醇的PR反应，但在重复给药后（第6 - 10天），只有联合用药使乙醇维持的反应持续降低。这些结果表明，在长期治疗后持续降低乙醇的强化作用方面，联合用药比单独使用托吡酯具有优势，并进一步支持其作为AUDs的潜在治疗方法的应用。
