Project 3: Influence of Mavoglurant on Alcohol Craving and Drinking in Heavy Drinkers Suchitra Krishnan-Sarin, Ph.D. Abstract One of the main goals of the Center for Translational Neuroscience on Alcoholism (CTNA) is to develop novel treatments for alcohol use disorders (AUDs). Understanding the neurochemical mechanisms underlying drinking behaviors is key to the development of treatments for AUDs. CTNA’s focus is on medications that target alcohol-related changes in the cortico-striatal circuitry, specifically the glutamatergic pathways that promote drinking through altering the balance between reward-related (model-based) and habitual (model-free) reinforcement. This project, P3, links the mechanisms studied in P1 and P2 to targeted clinical examinations of medications on alcohol drinking in heavy drinkers, and is a critical component of CTNA-5. We propose to examine the influence of mavoglurant (MAV), a negative allosteric modular (NAM) of the mGluR5 receptors, which may directly or indirectly (through NMDA receptors) normalize alcohol-induced disturbances in cortico-striatal glutamate signaling. Existing preclinical and clinical evidence suggest that mGluR5 receptors are upregulated by alcohol use, and preclinical evidence also suggests that mGLuR5 NAM’s reduce alcohol drinking and reinstatement of drinking after abstinence. We are fortunate to have access to MAV, a potent, selective, orally bioavailable mGluR5 NAM developed by Novartis, which is safe and tolerable in multiple neuropsychiatric populations. Our pilot evidence in social drinkers support the safety of MAV (200 mg/day), even when combined with alcohol, and suggests that MAV reduces intoxication from alcohol and brain responses to alcohol cues. P3 will examine the influence of MAV versus placebo on lapse-relapse to alcohol drinking among heavy drinkers with AUD. P3 is inherently innovative in both its conception and application because it identifies an important gap in clinical knowledge – if targeting mGluR5 receptors influences alcohol craving and drinking - and then brings to bear an experiment which combines a novel therapeutic agent (MAV) and two novel behavioral science tools, the Cue-Exposure Paradigm (CEP) and the Alcohol Drinking Paradigm (ADP) to investigate this question. P3 will address the primary questions of whether mavoglurant alters alcohol drinking and craving, and other alcohol effects, in the CEP and the ADP, and explore the associations of sex, family history of alcoholism and impulsivity to these changes. The project is served by the clinical and translational cores of the CTNA but also supports the goals of these cores to explore unique questions about how MAV changes model- free/model-based behaviors, and the role of polygenic risk scores in the effects of MAV.