# Neuroimmune mechanisms in stress and alcohol comorbidity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $475,633

## Abstract

Stress is a risk factor for alcohol use disorders (AUDs). Generally, individuals with anxiety disorders such
as posttraumatic stress disorder (PTSD) also have elevated rates of AUD, more severe alcohol withdrawal
symptoms, and greater relapse risk. Accumulating evidence indicates that immune-related pathways are
critical biological components of CNS function and dysfunction. Our published and preliminary results show
that canonical cytokines, such as Interleukin (IL)-18, have a profound capacity to affect neuronal function
and regulate GABA and glutamate transmission within the amygdala. Notably, IL-18 and its receptors are
highly expressed in the amygdala, a brain region that strongly contributes to anxiety- and addictive-related
behaviors, and stress history and alcohol exposure increase IL-18 expression. Recent studies in humans
found that IL-18 receptor gene expression is associated with distinct PTSD subtypes and that a single
nucleotide polymorphism (SNP) in the IL-18 gene (rs1946518) is associated with AUD in a highly
traumatized civilian cohort largely comorbid for PTSD. Notably, the same SNP in the IL-18 gene is also
associated with amygdala reactivity in anxiety. The goal of this proposal is to 1) identify the cellular
mechanisms underlying the essential role of IL-18 in homeostatic regulation of normal neuronal activities
and amygdala circuits, and 2) test the hypothesis that IL-18 signaling contributes to the development of
maladaptive stress-induced anxiety and AUDs. To accomplish our goal, we will employ innovative and
complementary techniques: behavior, electrophysiology, ribosome profiling combined with next generation
sequencing, in situ hybridization/RNAScope and immunohistochemistry, as well as pharmacological and
viral vector-mediated knock down of the IL-18 system in amygdala. We will determine the interactions of
peripheral and central immune elements in healthy and pathological function, comparing Vulnerable vs.
Resilient subjects, at the molecular, cellular, circuit and behavioral levels. We will identify the role of IL-18
signaling on synaptic functions in amygdala circuits in both male and female rats using an adapted “2-hit”
rat model of stress to generate escalated drinking and high anxiety-like phenotypes for behavioral and
physiological studies. Collectively, these studies will elucidate the mechanisms that drive IL-18
dysregulation to contribute to stress-induced anxiety and AUDs, and may identify promising targets for
treatment strategies for anxiety disorders and alcoholism.

## Key facts

- **NIH application ID:** 10650796
- **Project number:** 5R01AA027700-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** MARISA ROBERTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $475,633
- **Award type:** 5
- **Project period:** 2019-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10650796

## Citation

> US National Institutes of Health, RePORTER application 10650796, Neuroimmune mechanisms in stress and alcohol comorbidity (5R01AA027700-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10650796. Licensed CC0.

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