Glial cell function and ethanol reward

描述（由申请人提供）：酒精中毒与几种脑异常相关，包括神经胶质细胞减少（Korbo 1999; Miguel- Hidalgo et al. 2006）、多巴胺能神经传递失调（Tsai 1998）和神经元活性升高（De Witte et al. 2003）。由于神经胶质细胞在运输兴奋性神经递质谷氨酸中起着关键作用，因此这些病理可能是相关的。最近的报告表明，托吡酯（谷氨酸受体拮抗剂）可减少人类的复发（Baltieri et al. 2008）和实验室动物的应激诱导饮酒（Farook et al. 2009），从而表明谷氨酸能功能与酒精中毒治疗之间存在因果关系。此外，最近的研究表明，胶质细胞消融可增加大鼠的乙醇偏好（Miguel-Hidalgo等人，2008）。因此，越来越多的证据表明谷氨酸能传递和神经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，我假设减少神经胶质细胞谷氨酸运输与增加乙醇奖励。我将测试这一假设间接相关的神经胶质细胞数量与遗传背景，依赖程度，和饮酒模式，并直接使用药理学操作，防止谷氨酸贩运神经胶质细胞在收购乙醇的位置偏好，作为乙醇奖励的指标。虽然酒精中毒是由复杂的症状，酒精中毒的某些方面可以在动物模型中使用这些程序，包括依赖，饮酒和渴望。使用这些工具和显微注射技术，我将确定是否神经胶质细胞数量与乙醇摄入量和乙醇奖励是否由神经胶质谷氨酸传输调节。这些研究提供了一个动物模型的异常，存在于酗酒者，并试图确定他们是否有助于酒精中毒的病因。这是一种新的方法，将扩大我们对人类酒精中毒相关缺陷在啮齿动物乙醇奖励调节中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。 公共卫生相关性：拟议的研究旨在提高我们对酗酒原因的理解。这将通过探索与人类酒精中毒相关的神经胶质细胞缺陷在啮齿动物乙醇依赖和奖励调节中的相关性来实现。这项工作很有可能促进新的更有效的治疗策略的发展。

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.