# Neural Substrates of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $387,500

## Abstract

Summary
Although alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, little is
known about the neural substrates that contribute to this comorbidity. Moreover, despite the frequent co-
occurrence of AUD and PTSD, there is marked variability in the likelihood of developing these disorders and
even less is known about the neural substrates that might confer vulnerability or resilience to AUD and PTSD.
The scientific premise of this application is that a better understanding of the circuitry and neurobiology that
differentiate these vulnerable and resilient populations may reveal novel targets for the development of more
effective treatments for individuals suffering from the comorbid condition. To address this challenge, we have
extensively characterized a rodent model of early life stress, adolescent social isolation (aSI), and have
generated encouraging support for the face, construct and predictive validity of aSI as a model of vulnerability
to AUD and PTSD. For example, relative to rats group-housed throughout adolescence (aGH), aSI rats exhibit
many behaviors linked with heightened risk of AUD and PTSD, including deficits in fear extinction and enduring
increases in ethanol drinking behaviors. Notably, a relatively mild fear conditioning procedure significantly
increased ethanol self-administration in aSI rats for at least 8 weeks while having no effect on ethanol drinking
in aGH subjects. Published and ongoing neurobiological studies have identified profound adaptations that may
contribute to these behavioral phenotypes, including increased measures of excitability within the basolateral
amygdala (BLA) and ventral hippocampus (vHC), two highly interconnected brain regions that play an integral
role in many of the emotional behaviors that are disrupted in AUD and PTSD. Based on these findings, the
studies outlined in this application will employ a multidisciplinary experimental design to determine if the fear
conditioning procedure leads to the expression of core behavioral symptoms of AUD and PTSD in aSI rats and
whether aGH subjects will be resilient to this stressor. Neurobiological studies will determine if the fear
conditioning procedure exacerbates aSI-associated neurobiological adaptations in the BLA and vHC, and
specifically within the BLA-vHC circuit, and whether a strengthening of this circuit plays a causal role in
AUD/PTSD-like behavioral phenotypes promoted by this model. Additional studies will test a novel therapeutic
strategy to reverse the maladaptive behaviors promoted by aSI + fear conditioning. Based on other emerging
findings, these studies will also test the innovative hypothesis that aSI + fear conditioning promotes similar
neural adaptations in male and female rats but that the behavioral phenotypes engendered by these stressors
may be sexually dimorphic. Collectively, these studies will further strengthen the validity of aSI as a model of
heightened vulnerability to comorbid AUD an...

## Key facts

- **NIH application ID:** 9967910
- **Project number:** 5R01AA026551-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jeffrey L. Weiner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967910

## Citation

> US National Institutes of Health, RePORTER application 9967910, Neural Substrates of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder (5R01AA026551-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967910. Licensed CC0.

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