# Sex differences in neuroendocrine mechanisms of HPA axis dysfunction in alcohol use disorder

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $37,337

## Abstract

Project Summary
Alcohol use disorder (AUD) is a chronic relapsing disorder with unmet pharmacological needs,
characterized by compulsive alcohol seeking, excessive intake, and a negative emotional state.
The hypothalamic-pituitary- adrenal (HPA) axis which normally coordinates adaptive responding
to stressors, is often dysregulated in alcohol dependence. Consequently, alcoholics trying to
abstain have difficulty coping with stressful events which contributes to the high rates of relapse
observed in these individuals. The parvocellular neuroendocrine cells (PNCs) in the
paraventricular nucleus (PVN) of the hypothalamus serve as an integrative nexus for HPA axis
function, coordinating excitatory, inhibitory and endocrine signals to initiate HPA axis activation.
Acute stress was shown to induce synaptic plasticity in the form of short-term potentiation (STP)
at glutamatergic synapses onto the corticotropin releasing factor (CRF)-releasing PNCs. Our lab
has demonstrated that rats withdrawn from chronic intermittent ethanol treatment exhibit a loss
of stress-induced STP in PNCs, concomitant with blunted hormonal responses to repetitive
stress. Stress hormones and neurotransmitters such as CRF and norepinephrine appear as
likely candidates in gating stress-dependent HPA axis plasticity. Accordingly, I will further my
training in whole-cell patch clamp electrophysiology in ex vivo microdissected PVN slices to
assess the efficacy of pharmacological manipulation to normalize ethanol-induced maladaptive
phenotypes. While both males and females are capable of stress-induced STP in hypothalamic
CRF-releasing PNCs, potential sex-differences have not been adequately addressed.
Therefore, in Specific Aim 1 I will evaluate whether chronic ethanol-induced deficits to synaptic
plasticity in the PVN are sex-specific. Norepinephrine inputs are critical for the initiation and
maintenance of HPA activation. Thus, in Specific Aim 2 I will evaluate the specific contributions
of a1 and a2 adrenergic receptors through specific antagonists (prazosin and atipamezole,
respectively) to stress and ethanol-induced changes in PNC plasticity. These aims together will
test the hypothesis that sex differences in CRF and noradrenergic signaling underlies
differences in ethanol induced maladaptive HPA reactivity, contributing to the gross
population differences seen clinically in AUD. I have developed a rigorous and thorough
training regimen to achieve these electrophysiological endpoints allowing me to develop a
critical expertise in pharmacology and physiology, by which I can help bring pharmaceutical
interventions to patients in need. The plan is supported by a highly capable team of mentors to
facilitate my training and career development under the proposed award period.

## Key facts

- **NIH application ID:** 10068983
- **Project number:** 1F31AA028183-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Joseph Munier
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,337
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068983

## Citation

> US National Institutes of Health, RePORTER application 10068983, Sex differences in neuroendocrine mechanisms of HPA axis dysfunction in alcohol use disorder (1F31AA028183-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068983. Licensed CC0.

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