# mGlu5 modulation prevents and attenuates deficits in a model of PTSD/AUD comorbidity

> **NIH VA I01** · JAMES H QUILLEN VA MEDICAL CENTER · 2024 · —

## Abstract

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two of the most common mental
health disorders and are highly comorbid. Unfortunately, the incidence rate of PTSD is significantly greater in
the Veteran population. Even worse, Veterans with PTSD are almost twice as likely to develop issues with alcohol
abuse and AUD. Both disorders are thought to arise from “aberrant learning” resulting in deficits in the ability to
adjust behavior (e.g. impaired cognitive flexibility) that ultimately drives continued drug abuse or fear behavior.
Recent evidence further suggests that the neurocircuitry of fear and anxiety disorders and the neurocircuitry of
drug addiction have many common characteristics. A prominent feature of both disorders is dysfunctional top-
down control of behavior by the prefrontal cortex (PFC). Alterations in prefrontal-mediated cognitive processes
that regulate behavior likely contribute to the high comorbidity of the disorders. Of particular clinical importance,
this comorbidity is associated with significantly worse prognosis of recovery when compared to non-comorbid
individuals. There is also evidence that PTSD symptoms are a significant risk factor for development of AUD
that, in turn, interfere with PTSD treatment and contributes to increased functional impairment. This application
will examine three separate aims that contain novel questions about PTSD/AUD comorbidity and utilize state-of-
the-art techniques to answer them. We propose that the combination of stress and alcohol exposure alters many
factors associated with the disorder including drug use, relapse behavior, cognitive deficits, and vulnerability to
future traumas. The overarching hypothesis of this proposal is that stress and alcohol exposure alter subsequent
drug, cognitive, and stress-related behaviors through glutamatergic mechanisms in subregions of the PFC. To
test this, we will use a multi-faceted approach that incorporates behavioral pharmacology, optogenetics, and
telemetry to investigate the interactions between a traumatic stressor and chronic alcohol exposure to identify
certain brain mechanisms that may mediate the resulting changes in behavior. Aim 1 will examine the result of
stress and chronic exposure on alcohol-related behaviors including intake, relapse-like behavior, and
consolidation of extinction memories. We will use recent developments in technology to monitor some of the
same measurements in rats that are often used in human studies. Radiotelemetry sensors will be implanted in
the rats to determine whether stress-induced alterations in alcohol behaviors are associated with deficits in heart
rate variability (HRV: a physiological measure that reflects coping ability). In this aim, and the remaining aims,
will attempt to either attenuate or prevent stress- and alcohol-induced behavioral deficits through manipulation
of glutamatergic signaling in the PFC and its projections to other brain regions. Finally, to better underst...

## Key facts

- **NIH application ID:** 10768545
- **Project number:** 5I01BX005367-03
- **Recipient organization:** JAMES H QUILLEN VA MEDICAL CENTER
- **Principal Investigator:** Justin T Gass
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768545

## Citation

> US National Institutes of Health, RePORTER application 10768545, mGlu5 modulation prevents and attenuates deficits in a model of PTSD/AUD comorbidity (5I01BX005367-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768545. Licensed CC0.

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