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）功能的神经调节可能比DA受体阻滞剂更有效地治疗酒精依赖，并且与这一假设一致，我们已经表明昂丹司琼是一种5-羟色胺-3拮抗剂，主要在腹侧被盖区和背侧核（NAc）调节CMDA，是对酒精依赖型人类亚型的有效治疗，具有高的疾病生物负荷。我们还证明，托吡酯，一种GABA/谷氨酸（GLU）调节剂，被认为是产生广泛的抑制CMDA，是一种有效的治疗酒精依赖个体的异质组。由于昂丹司琼和托吡酯通过不同的神经元过程表现出它们的作用，两者都导致CMDA功能的调节，因此可以合理地假设它们的组合在治疗酒精依赖中比单独使用更有效。因此，我们建议使用不同的大鼠自我给药模型和品系来表征昂丹司琼和托吡酯单独和联合使用时发挥其行为和神经化学作用的机制过程。在目标1和目标2中，我们将检查昂丹司琼和托吡酯单独使用和联合使用将减少乙醇强化的预测，在目标2和目标3中，我们将检查昂丹司琼和托吡酯单独使用和联合使用将减少乙醇恢复的预测。预计该组合与乙醇强化和恢复的增加或协同降低以及CMDA和GLU浓度的相关调节相关。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，因为它侧重于确定两种潜在药物昂丹司琼和托吡酯治疗酒精依赖的生物学基础。这项基础科学工作的总体目标是帮助确定可能非常适合用这两种药物治疗酒精依赖的人群，并提供可能指导开发更有效药物的信息。

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.