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

> **NIH NIH P50** · YALE UNIVERSITY · 2024 · $207,092

## Abstract

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.

## Key facts

- **NIH application ID:** 10837131
- **Project number:** 5P50AA012870-24
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** GODFREY D PEARLSON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $207,092
- **Award type:** 5
- **Project period:** 2001-06-04 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837131

## Citation

> US National Institutes of Health, RePORTER application 10837131, Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor, Mavoglurant. (5P50AA012870-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10837131. Licensed CC0.

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