There is overwhelming evidence now to support a role for endocannabinoid signaling [anandmide, AEA and cannabinoid (CB1 receptor)] in many aspects of alcohol-related behaviors. The objective of the proposed research is to investigate the role of endogenously found marijuana like brain constituent anandamide (AEA) and its receptor (CB1) in voluntary ethanol (EtOH) consumption and withdrawal. The proposed research utilizes Sardinian EtOH-preferring (sP) and EtOH-nonpreferring (sNP), one of the very few unique pairs of rat lines worldwide, developed by our Italian colleagues for opposite EtOH-preference and consumption. The proposed research tests the hypothesis that genetically predetermined differences in brain regional endocannabinoid signaling which affects the neurotransmitter release and neurtransmision, contributes to the opposite EtOH drinking behavior and development of EtOH-preference and aversion. The proposed research will test this hypothesis with the following specific aims; (1) investigate the changes in AEA and 2-arachidonyl glycerol (2-AG), and CB1 receptor distribution and function, in various brain regions (cerebellum, cerebral cortex, hippocampus and striatum), implicated in reward and reinforcement circuitry, in (a) EtOH naive sP and SNP rats and (b) before and during acquisition and maintenance of voluntary EtOH-drinking and in correspondence of """"""""EtOH-deprivation effect"""""""" (withdrawal) in sP rats and (2) determine the effect of pharmacological manipulation with SR141716, a CB1 receptor antagonist on endocannabinoid signaling in these brain regions of sP rats before and during acquisition and maintenance of voluntary EtOH drinking and in correspondence of """"""""alcohol deprivation effect"""""""" (withdrawal). The findings of this study will lead to better understanding of the mechanisms underlying voluntary EtOH consumption and withdrawal and to development of drug therapies using endocannabinoid targeted drugs to treat problems associated with alcohol abuse and alcoholism.
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