Withdrawal in human alcoholics is associated with increased anxiety and depression that can be alleviated through continued drinking. It is belived that these negative affective states constitute a major driving force for continued alcohol consumption. Recent data gathered in experimental animals suggests that endogenous cannabinoids play an important role in regulating anxiety-related behaviors. It is theorized that the endocannabinoid system is activated in response to anxiogenic situations, and that this activation serves to dampen neuronal responses contributing to anxiety-like behavior. A growing body of evidence also shows that ethanol exposure alters brain endocannabinoid (eCB) levels and that chronic ethanol exposure induces persistent changes in the function of this system. We have recently observed that interstitial levels of the eCB substances anandamide and 2-arachidonoylglycerol (2-AG) are significantly decreased in the central nucleus of the amygdala (CeA) during acute withdrawal from chronic ethanol exposure. Moreover, resumption of ethanol intake restores 2-AG levels back to pre-withdrawal baseline levels. Based on the proposed role of eCBs as mediators of """"""""anti-stress"""""""" effects, these findings suggest that deficient eCB signaling in the CeA may underlie a sensitized anxiety-like phenotype thought to contribute to excessive ethanol consumption. The experiments proposed in this Component will employ in vivo neurochemical monitoring and behavioral pharmacology to characterize the potential involvement of deficient eCB signaling in the CeA in the motivational effects of ethanol withdrawal. Experiments in the first Specific Aim will characterize the effect of ethanol dependence and withdrawal on basal and stress-induced eCB function in the CeA using in vivo microdialysis. Experiments in the second Specific Aim will utilize behavioral testing to characterize the involvement of altered eCB function in the CeA in the increased anxiety-like behavior and excessive ethanol consumption observed in ethanol-dependent rats. The proposed experiments will evaluate interactions between eCBs, GABA and glutamate in the CeA and therefore this work is highly related to the work proposed in the Cellular Neurobiology Research Component (Roberto/Siggins). The results obtained in this research component may provide important new insight into the neural mechanisms that propel alcohol addiction.
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