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.