Glial cell function and ethanol reward

描述(申请人提供)：酒精中毒与几种大脑异常有关，包括神经胶质细胞减少(Korbo 1999；Miguel-Hidalgo等人)。谷氨酸能神经传递失调(Tsai，1998)，以及神经元活性升高(De Witte等人。2003年)。因为神经胶质细胞在兴奋性神经递质谷氨酸的运输中起着关键作用，所以这些病理很可能是相关的。最近的报告表明，谷氨酸能功能和酒精中毒的治疗之间存在因果联系，因为它证明了谷氨酸受体拮抗剂托吡酯可以减少人类的复发(Baltieri等人)。2008)和应激诱导的实验动物饮酒(Farook等人。2009年)。此外，最近的工作表明，胶质细胞消融可以增加大鼠对酒精的偏好(Miguel-Hidalgo等人。2008年)。因此，越来越多的证据表明，谷氨酸能传递和胶质细胞功能可能在情绪障碍的病理生理学和缓解中发挥重要作用。基于这些观察，我假设减少胶质细胞谷氨酸的运输与增加乙醇奖励有关。我将通过将神经胶质细胞数量与遗传背景、依赖程度和饮酒模式相关联，并直接使用药物操纵来间接检验这一假设，这些药物操纵阻止神经胶质细胞在获得酒精位置偏好时转移谷氨酸，作为酒精奖励的指标。虽然酒精中毒是由复杂的症状组成的，但酒精中毒的某些方面可以在动物身上使用这些程序进行建模，包括依赖、饮酒和渴望。使用这些工具和显微注射技术，我将确定神经胶质细胞数量是否与酒精摄入量有关，以及酒精奖励是否受神经胶质谷氨酸传输的调节。这些研究为酗酒者存在的异常提供了一个动物模型，并试图确定它们是否与酒精中毒的病因有关。这是一种新的方法，将拓宽我们对与人类酒精中毒相关的缺陷在调节啮齿动物乙醇奖励方面的病理生理学相关性的理解，这很有可能促进新的更有效的治疗策略的发展。 与公共健康相关：拟议的研究旨在加强我们对酒精中毒原因的了解。这将通过探索与人类酒精中毒有关的胶质细胞缺陷在调节啮齿类动物的酒精依赖和奖赏中的相关性来实现。这项工作极有可能促进新的更有效的治疗策略的开发。

DESCRIPTION (provided by applicant): Alcoholism is associated with several brain abnormalities, including fewer glial cells (Korbo 1999; Miguel- Hidalgo et al. 2006), dysregulated glutamatergic neurotransmission (Tsai 1998), and elevated neuronal activity (De Witte et al. 2003). Because glial cells play a key role in trafficking the excitatory neurotransmitter glutamate, it is likely that these pathologies are related. Recent reports suggest a causal link between glutamatergic function and the treatment of alcoholism by demonstrating that topiramate, an antagonist at glutamate receptors, reduces relapse in humans (Baltieri et al. 2008) and stress-induced drinking in laboratory animals (Farook et al. 2009). In addition, very recent work suggests that glial ablation can increase ethanol preference in rats (Miguel-Hidalgo et al. 2008). Thus, there is mounting evidence that glutamatergic transmission and glial cell function may play important roles in both the pathophysiology and relief of mood disorders. Based on these observations, I hypothesize that reduced glial glutamate trafficking is associated with increased ethanol reward. I will test this hypothesis indirectly by correlating glial cell number with genetic background, degree of dependence, and drinking patterns and directly using pharmacological manipulations that prevent glutamate trafficking by glial cells in the acquisition of ethanol place preference, as an index of ethanol reward. Although alcoholism is made up of complex symptoms, some aspects of alcoholism can be modeled in animals using these procedures including dependence, drinking, and craving. Using these tools and microinjection techniques, I will determine if glial cell number is associated with ethanol intake and whether ethanol reward is regulated by glial glutamate transmission. These studies provide an animal model of abnormalities that are present in alcoholics and seek to determine whether they contribute to the etiology of alcoholism. This is a novel approach that will broaden our understanding of the pathophysiological relevance of deficits that are associated with alcoholism in humans in the regulation of ethanol reward in rodents, which has a high likelihood of facilitating the development of new more effective treatment strategies. PUBLIC HEALTH RELEVANCE: The proposed studies seek to enhance our understanding of the causes of alcoholism. This will be accomplished by exploring the relevance of glial cell deficits that are associated with alcoholism in humans in the regulation ethanol dependence and reward in rodents. This work has a high likelihood of facilitating the development of new more effective treatment strategies.