Rat Models of Alcohol Dependence for Evaluating Combined Medication Effects

描述(申请人提供)：皮质中脑边缘多巴胺(CMDA)功能的神经调节对于酒精依赖的治疗可能比DA受体阻断更有效，与这一假设一致，我们已经证明恩丹西酮是一种主要在腹侧被盖区和伏隔核(NAC)调节CMDA的5-羟色胺-3拮抗剂，是治疗具有高生物负荷的酒精依赖患者的一种亚型。我们还证明了托吡酯是一种GABA/谷氨酸(GLU)调节剂，被认为能产生广泛的CMDA抑制作用，是一种对不同种类的酒精依赖个体的有效治疗。由于恩丹西酮和托吡酯通过不同的神经元过程表现出它们的作用，都导致了CMDA功能的调节，因此有理由假设，在治疗酒精依赖方面，它们联合使用比单独使用更有效。因此，我们建议使用不同的大鼠自我给药模型和品系来描述恩丹西酮和托吡酯单独和联合应用发挥其行为和神经化学效应的机制。在目标1和2中，我们将检验恩丹西酮和托吡酯单独和联合使用将减少乙醇强化的预测，在目标2和3中，我们将检验恩丹西酮和托吡酯单独和联合使用将减少乙醇恢复的预测。这一组合预计将与乙醇强化和恢复的增加或协同减少以及CMDA和GLU浓度的相关调节有关。这种药物-行为反应模式或“指纹”将使我们能够识别未来有希望的具有类似效果的推定药物，并使我们能够了解它们的哪些特性可以被利用来开发更有效的药物。公共卫生相关性我们的研究意义重大，因为它专注于确定两种潜在药物恩丹西酮和托吡酯治疗酒精依赖效果的生物学基础。这项基础科学工作的总体目标是帮助确定可能最适合使用这两种药物治疗酒精依赖的人群，并提供可能指导更有效药物开发的信息。

DESCRIPTION (provided by applicant): Neuromodulation of cortico-mesolimbic dopamine (CMDA) function may be more effective for the treatment of alcohol dependence than DA receptor blockade, and consistent with this hypothesis, we have shown that ondansetron a serotonin-3 antagonist that modulates CMDA primarily in the ventral tegmental area and nucleus accumbens (NAc), is efficacious treatment for a subtype of alcohol dependent humans with high biological loading for the disease. We have also demonstrated that topiramate, a GABA/glutamate (GLU) modulator that is believe to produce widespread suppression of CMDA, is an efficacious treatment for a heterogeneous group of alcohol dependent individuals. Because ondansetron and topiramate manifest their effects through different neuronal processes, both resulting in modulation of CMDA function, it is reasonable to hypothesize that their combination shall be more efficacious than either alone in the treatment of alcohol dependence. Therefore, we propose to characterize the mechanistic process by which ondansetron and topiramate, both alone and in combination, exert their behavioral and neurochemical effects using different rat self-administration models and strains. In Aim 1 and 2 we will examine the prediction that both ondansetron and topiramate alone and in combination will reduce ethanol reinforcement, and in Aim 2 and 3 we will examine the prediction that both ondansetron and topiramate alone and in combination will reduce ethanol reinstatement. The combination is expected to be associated with added or synergistic decreases in ethanol reinforcement and reinstatement as well as associated modulation in CMDA and GLU concentrations. This pharmaco-behavioral response pattern or "finger-print" will enable us to identify future promising putative medications with similar effects as well as enable us to understand which of their properties can be harnessed to develop even more potent medications. PUBLIC HEALTH RELEVANCE Our study is significant because it focuses on determining the biological basis for the effects of two potential medications, ondansetron and topiramate, for treating alcohol dependence. The overall goals of this basic science work is to helping to identify populations that may be ideally suited for treating alcohol dependence with these two medications, and to provide information that may guide the development of even more effective medications.