PROJECT SUMMARY People in recovery from alcohol use disorder (AUD) can experience a range of physiological and behavioral effects during withdrawal. These effects include aberrant food consumption, and increased alcohol drinking and seeking, which can increase stress and drive relapse. Ethanol dependence appears to dysregulate the glucagon- like peptide-1 (GLP-1) system, and clinical drugs that target this system are now being investigated for their ability to reduce food and alcohol intake. While GLP-1 is a gut peptide, it is also a neuropeptide, synthesized by neurons of the nucleus tractus solitarius (NTS), and its receptor (GLP-1R) is expressed throughout the brain. Several clinically approved GLP-1R agonist medications cross the blood brain-barrier, and work both peripherally and centrally. While these medications hold promise, they also induce undesirable side-effects, largely due to their effects in the hindbrain. Specific targeting of GLP-1Rs in regions of the forebrain could reduce the off-target effects of GLP-1 medications, while still suppressing aberrant food and alcohol consumption during AUD recovery. Thus, this proposal is designed to investigate the ability of GLP-1R in discrete CNS circuits to regulate binge-like food and ethanol intake and relapse during withdrawal. We will model ethanol dependence using chronic intermittent ethanol (CIE) exposure by vapor inhalation to test the overarching hypothesis that withdrawal from ethanol in the CIE model leads to physiological dysregulation, including dysregulation of the central GLP-1 system and associated disruption in reward taking and seeking. Thus, by increasing GLP-1R activity in the prefrontal cortex (PFC) and paraventricular nucleus of the thalamus (PVT), we can suppress CIE-induced behavioral dysregulation, including escalated binge-like eating and ethanol drinking, and reinstatement of seeking for palatable food and ethanol. Aim 1 is to examine the consequences of withdrawal from CIE on binge- l