Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor Mavoglurant

This project explores the effects of 1 dose of Mavoglurant, an experimental non-competitive antagonist to metabotropic glutamate receptor-5 (mGlur5) developed by Novartis, in a double-blind, randomized, counterbalanced manner on alcoholism risk-relevant tasks. Drug/placebo will be administered on 2 separate visits separated by 1 week. More specifically, this project examines 4 functional MRI tasks related to different aspects of reward and/or impulsivity-related behavior in different contexts, compares the underlying neural circuitry across tasks, and uses a pharmacologic probe of the glutamatergic system to examine N-methyl-D-Aspartate and Dopamine (NMDA/DA) interactions. The combined measures provide the opportunity to advance our understanding of specific aspects of brain function related to familial alcoholism vulnerability in an already well characterized population as some members evolve into alcohol abuse. In addition, as well as conventional within-task analyses, functional network connectivity and allied approaches will be used to examine brain networks across the tasks.

Inclusion criteria

• Ages 18-45 years
• Estimated full-scale IQ>70
• Individual can cooperate with all study procedures
• No history of neurological disorder (e.g., epilepsy)
• No major medical condition (e.g., cancer)
• No history of significant head trauma
• Stable medication treatment 6 weeks prior to study enrollment
• Negative urine drug and breathe alcohol test at time of MRI scan
• Negative urine pregnancy test at time of MRI scan
• No MR contra-indications (e.g., in-body metal implant, severe claustrophobia)
• No contra-indications to study drug

Exclusion criteria

• A diagnosis of any psychotic disorder, or current mood or anxiety disorders under DSM-V, using the SCID-V-RV psychiatric interview
• A current diagnosis of: a) Alcohol use disorder, if severe (AUD, mild or moderate OK if no craving, tolerance, and withdrawal 3 months prior to interview) b) Substance use disorder
• Report of psychotic disorder in a 1º relative
• Auditory or visual impairment that interferes with test-taking
• Prenatal exposure to alcohol plus currently meeting criteria for features of fetal alcohol syndrome
• Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English > grade 1
• Intellectual Disability (Full Scale IQ<70)
• Traumatic brain injury with loss of consciousness > 30 minutes or concussion in last 30 days
• Presence or history of neurosurgery or any neurologic illness that may affect brain physiology (e.g., epilepsy, Multiple Sclerosis), including focal brain lesion seen on structural MRI (all structural scans are read by a board certified radiologist)
• A current major medical condition (e.g. cancer, heart failure)
• Current pregnancy (all females will be tested with urine screens on the day of MRI)
• Women not on an effective form of birth control/contraception or abstinent during time of study visits to prevent exposure of the investigational drug to suspected fetus
• Current substance use with the exception of marijuana (THC), provided last use of THC was 24+ hours before visit (All participants will receive a urine screen for the presence of marijuana, cocaine, opiates and a breath screen to detect the presence of alcohol)
• Inability to comprehend the consent form appropriately
• Inability to cooperate with study procedures
• Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital xray performed if needed)