P2: Pearlson, Stevens. Functional neuroimaging of alcoholism vulnerability: probing glutamate and reward using the mGluR5 inhibitor mavoglurant. Alcohol use disorder (AUD) is prevalent and a major cause of morbidity and mortality; a portion of the risk for the condition is familial. A significant portion of inherited risk for AUD likely involves dominance of glutamate over dopamine in brain circuits governing certain types of reward responsiveness, impulsivity and learning. Project 2 will use the mGluR5 negative allosteric modulator drug mavoglurant as a probe in conjunction with 4 functional MRI paradigms to understand how the drug targets the brain systems implicated in familial alcoholism risk. These fMRI paradigms are 1. Response to rewards and punishments (monetary incentive delay task, MID), 2. Inhibiting response to prepotent cues (go/no-go task, GNG), 3. Responsiveness to alcohol-related as opposed to soft-drink or neutral cues (alcohol cue reactivity task, ACR) and 4. the ability to benefit from “model-based,” goal-directed learning strategies versus “model-free” learning, that is a less advantageous strategy involving dominance of immediate rewards or habit over behavior (multi-stage decision-making, MSDM task). This project will compare equal numbers of individuals who have strong positive family history of alcoholism and are thus at increased risk for the disorder (family history positive or FHP) to those who have no affected relatives (family history negative or FHN). We will compare fMRI-assessed brain responses during task performance following single doses of mavoglurant and placebo, administered under double-blind, randomly assigned, cross- over conditions, at 2 separate visits. We predict that on placebo FHP will: 1. Be overly- responsive to rewards on the MID, 2. Show different brain signaling during performance of the GNG and ACR, and 3. Manifest an instrumental learning bias on the MSDN accompanied by altered relationships between nucleus accumbens and medial frontal cortex. Unifying these predictions, we also hypothesize 4. That in the case of MID, ACR and MSDM, but not the GNG, these altered brain circuit relationships in FHP will be restored by the study drug mavoglurant such that they more closely resemble patterns seen in FHN in the placebo condition. The use of variants of the MSDM task provides a useful conceptual link that binds the three major CTNA projects together, offering the opportunity to link understanding of neural circuits related to AUD, alcoholism risk and alcohol-related learning bias in a specific, focused, neurotransmitter receptor hypothesis-driven context.