# Extended amygdala mGlu8 receptor signaling in stress-reward interactions

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2022 · $31,511

## Abstract

Project Summary
Exposure to chronic stress has been implicated in numerous psychiatric conditions such as PTSD, depression,
addiction and anxiety, and exposure to stressful experiences are one of the most common causes of drug
relapse. The Bed Nucleus of the Stria Terminalis (BNST) mediates many anxiety- and stress-responses that
drives relapse and the addictive cycle characteristic of substance use disorders. Post-synaptic Gi-coupled
GPCR signaling in the BNST (via Gi-DREADDs and α2A adrenoreceptors on non-noradrenergic Adra2a+
neurons) is sufficient to increase neuronal activity and drive drug-dependent behaviors, while pharmacological
blockade or avoidance of post-synaptic receptor activation decreased neuron activity and cocaine-dependent
behavior. The Gi-coupled metabotropic glutamate (mGlu) receptor subtype 8, implicated in numerous
psychiatric conditions such as substance use disorders, is co-expressed on this population of Adra2a+ BNST
cells. Efforts targeting adrenergic signaling to prevent relapse have been largely unsuccessful, highlighting the
need for innovative therapeutic targets. Interestingly, systemic mGlu8 activation induces cfos expression, a
marker of neuron activity, in stress-sensitive brain regions, suggesting that mGlu8 modulation may be a means
by which to alter BNST activity to prevent stress-induced relapse. In Specific Aim 1, I will begin to investigate
the effects of mGlu8 signaling on measures of BNST activity using convergent anatomical and
pharmacological mapping strategies. In Specific Aim 2, I will assess the effect of BNST mGlu8 KO on gross
anxiety measures as well as in our cocaine conditioned place preference and reinstatement assays to test the
sufficiency of this receptor in driving stress-sensitive behaviors. Furthermore, I will analyze the stress-induced
activity of DCPG-sensitive neurons through the use of fiber photometry and in vivo optogenetics. Together,
these aims will examine our hypothesis that mGlu8 positively modulates the activity of a pro-reinstatement
population of BNST neurons and that mGlu8 signaling is functionally necessary for cocaine reinstatement. In
doing so, we hope to identify novel therapeutic targets that will serve to decrease the instance of stress-
induced relapse and improve the treatment outcomes of the patients currently struggling with substance use
disorders.

## Key facts

- **NIH application ID:** 10440273
- **Project number:** 5F31DA054774-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Bretton Nabit
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,511
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440273

## Citation

> US National Institutes of Health, RePORTER application 10440273, Extended amygdala mGlu8 receptor signaling in stress-reward interactions (5F31DA054774-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440273. Licensed CC0.

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