Rat Models of Alcohol Dependence for Evaluating Combined Medication Effects

用于评估综合药物效应的酒精依赖大鼠模型

• 批准号: 7527804
• 负责人: Wendy Jean Lynch
• 金额: $ 35.14万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527804
• 关键词: Abstinence; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Basic Science; Behavioral; Biological; Brain region; Breeding; Clinical; Clinical Research; Development; Development, Other; Disease; Dopamine; Ethanol; Fingers; Future; Genetic; Genetic Load; Glutamates; Goals; Heavy Drinking; Human; Individual; Ion Channel; Measurement; Measures; Medial; Mediating; Microdialysis; Modeling; Neurons; Nucleus Accumbens; Ondansetron; Pattern; Personal Satisfaction; Pharmaceutical Preparations; Population; Prefrontal Cortex; Printing; Procedures; Process; Property; Public Health; Rattus; Research; Self Administration; Serotonin; Signal Transduction; Site; Synapses; Testing; Ventral Tegmental Area; Western Blotting; Wistar Rats; Work; alcohol effect; alcohol reinforcement; alcohol seeking behavior; base; dopaminergic neuron; gamma-Aminobutyric Acid; neuroadaptation; neurochemistry; preference; receptor; response; topiramate

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.

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依赖酒精的人的亚型，该疾病具有高生物负荷。我们还证明，托托拉mate是一种GABA/谷氨酸（GLU）调节剂，它被认为可以广泛抑制CMDA，是对异构依赖酒精的个体的有效治疗方法。由于ondansetron和topiramate通过不同的神经元过程表现出它们的作用，这两者都会导致CMDA功能的调节，因此合理地假设它们的组合应比单独治疗酒精依赖性更有效。因此，我们建议表征on Dansetron和tupiramate（单独和组合）使用不同的大鼠自我给药模型和菌株发挥其行为和神经化学作用的机械过程。在AIM 1和2中，我们将研究以下预测：单独和结合组合的Ondansetron和托吡酯都会减少乙醇的增强，在AIM 2和3中，我们将研究以下预测：单独的Ondansetron和topiramate单独使用以及组合将减少乙醇的恢复。预计该组合将与乙醇增强和恢复原状以及CMDA和GLU浓度的相关调节相关。这种药物行为反应模式或“手指印刷”将使我们能够确定具有相似作用的未来有前途的推定药物，并使我们能够理解它们的哪些特性可以利用以开发出更有效的药物。公共卫生相关性我们的研究很重要，因为它专注于确定两种潜在药物（Ondansetron和tupiramate）对酒精依赖的影响的生物学基础。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的开发的信息。