# Partial mGlu5 Negative Allosteric Modulators to Prevent Relapse to Cocaine Abuse

> **NIH NIH R00** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $248,999

## Abstract

PROJECT SUMMARY/ABSTRACT
 Cocaine abuse, for which there are no FDA-approved pharmacological treatments, is associated with long-
term neurobiological and functional alterations underlying decreased affect/motivation, impaired decision-
making, sleep disturbances, and an exaggerated response to cocaine-related cues that are associated with
high rates of relapse. Human imaging studies report a state of “hypofrontality” (e.g. reduced blood oxygen level
dependent [BOLD] activation in the prefrontal cortex [PFC] in response to cognitive challenge), yet increased
response (e.g. increased BOLD response) to cocaine-related cues in abstinent cocaine users. Preclinical
studies provide evidence that altered mesocorticostriatal glutamatergic (Glu) signaling underlies some of these
changes. For example, increased glutamate-mediated synaptic plasticity in the PFC, NAc and ventral
tegmental area (VTA) are present following extended cocaine self-administration (SA). Exposure to cocaine-
related cues increases Glu (via cortico-accumbal) and DA concentrations (via cortico-VTA driven DA release)
in the NAc and attenuating these enhanced responses in the NAc represents a promising avenue for relapse
prevention. Inhibiting Glu function via negative allosteric modulation (NAM) of the metabotropic glutamate
(mGlu) receptor subtype, mGlu5 attenuates cocaine self-administration (SA) and cue-induced reinstatement of
cocaine-seeking behavior in rodents and nonhuman primates. The overall goals of the proposed studies are to
1) understand functional and neurochemical changes in the PFC and NAc in awake rats at rest and in
response to cocaine-related cues during abstinence following a cocaine self-administration (SA) regimen that
models compulsive drug use (6-h long access SA); and 2) test the hypothesis that inhibition of glutamatergic
function via mglu5 NAMs will attenuate the behavioral, functional and neurochemical response to cocaine-
paired conditioned cues that contribute to relapse. The proposed studies will systematically assess functional
and neurochemical changes in the cortico-accumbal circuit related to cue-induced reinstatement (preclinical
model of relapse), by utilizing fMRI and microdialysis techniques in awake rats.
 The studies proposed during the K99 phase of the application will examine the effects of the full mGlu5
NAM VU0409106 on cue-induced reinstatement, cue-induced changes in BOLD response (Aim 1) and on cue-
induced changes in Glu and DA concentrations in the PFC and NAc using microdialysis (Aim 2). These studies
will provide the applicant with the expertise to independently establish and conduct awake fMRI and
microdialysis studies in awake rats. In the studies proposed in Aims 3 and 4 (R00 portion) the applicant will test
the hypothesis that newly developed and characterized partial mGlu5 NAMs, compared to full mGlu5 NAMs, will
be equally effective in attenuating cue-induced reinstatement and the underlying neurochemical and functional
correlate...

## Key facts

- **NIH application ID:** 10002210
- **Project number:** 5R00DA042129-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert Warren Gould
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002210

## Citation

> US National Institutes of Health, RePORTER application 10002210, Partial mGlu5 Negative Allosteric Modulators to Prevent Relapse to Cocaine Abuse (5R00DA042129-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10002210. Licensed CC0.

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