Alcohol exposure reverses fear conditioning-induced change in endocannabinoid signaling

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Alcohol exposure reverses fear conditioning-induced change in endocannabinoid signaling Post-traumatic stress disorder (PTSD) is a severe anxiety disorder characterized by a cluster of symptoms including intrusive memories and hyper-arousal and reactivity. Maladaptive fear learning is one of the possible mechanisms underlying disease pathology. Endocannabinoids, lipid neuromodulators, control several physiological processes such as memory and mood are found to be altered in PTSD patients. PTSD patients exhibit lower circulating endocannabinoids and increased level of cannabinoid receptor 1. Hence, cannabinoid receptor agonists have been used to alleviate symptoms of PTSD. Nearly half of patients suffering from PTSD meet the criteria for alcohol use disorder (AUD). Alcohol exposure has been shown to increase endocannabinoids in several areas of the brain. This raise the possibility that decrease in endocannabinoid signaling is not only involved in PTSD, but may also cause alcohol reinforcement. Mounting evidence has implicated cerebellum in fear learning, emotional learning, and reward. My preliminary results show that the fear conditioning increases monoacyl glycerol (MAGL) activity increasing endocannabinoid degradation in the cerebellum. In contrast, chronic alcohol exposure decreases MAGL activity. Our central hypothesis is that fear conditioning elevates MAGL activity and reduces eCB tone, which promotes retention of fear memories, while subsequent alcohol exposure reverses these changes in the cerebellum. Aim 1 investigate the mechanisms of increased MAGL activity. Aim 2 will study the mechanisms by which alcohol exposure reduces MAGL activity using depolarization suppression of excitation and enzyme activity assay. Aim 2 will also investigate the effect of chronic alcohol exposure on fear memory retention. This study will provide mechanistic insight about PTSD comorbid AUD, which may lead to development of new therapeutics for this comorbidity.