# Exploring Potential Sex Differences In Neurobiological Mechanisms of Alcohol Sensitivity and Tolerance

> **NIH NIH R33** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $703,996

## Abstract

Project Summary
 Evidence from our lab and others finds that an individual's sensitivity to alcohol in emerging
adulthood predicts future alcohol-related problems. Although sensitivity has been hypothesized to relate to
alcohol tolerance, few studies have adequately evaluated that relationship. In addition, our prior research has
identified the prefrontal cortex (PFC) and limbic-hypothalamic-pituitary-adrenal (LHPA) stress axis, which
interact with the brain's reward circuit, as a potential sex-sensitive functional brain network associated with a
person's low level of response (LR) to alcohol. Until now, functional magnetic resonance imaging (fMRI)-based
associations with LR have analyzed brain regional alcohol effects in a segregated manner and did not consider
the functional connectivity (FC) between the PFC-LHPA network and sex differences in these brain circuits.
 The goals of this proposal are to conduct a series of post-hoc secondary analyses, two pilot feasibility
trials, and a full human laboratory study that combines neuroendocrine and ethanol-fMRI approaches to probe
the PFC-LHPA network through a lens focused on LR, alcohol's stimulating effects, the development of acute
tolerance, and potential sex differences. We hypothesize that low LR to alcohol will be correlated with
decreased FC between the PFC-LHPA network and that disrupted FC will be greater in women than men.
 To test this hypothesis, in the R21 phase we will reanalyze fMRI data from an existing data set wherein
low- and high-LR women and men completed an alcohol challenge followed by an ethanol/placebo-fMRI
emotional processing task. We will also explore potential sex differences and the relations among LR to
alcohol with: 1) acute tolerance measured previously in the lab, and 2) the subsequent development of chronic
tolerance measured longitudinally in two unique existing data sets. Finally, we will conduct two pilot feasibility
studies in 12 low- and high-LR women and men that will serve as Go / No-Go decision points for the R33
phase: 1) examine subjective and objective alcohol sensitivity measures and acute tolerance to a higher dose
of alcohol; and 2) examine alcohol's effects on brain activation and connectivity patterns following emotional-
and stress-processing fMRI tasks that stimulate different components of the PFC-LHPA network.
 In the R33 phase, we will conduct a new set of experiments combining a higher-dose ethanol
neuroendocrine challenge piloted in the R21 phase followed by the ethanol/placebo-fMRI procedure piloted
previously in 60 young, moderate drinking, non-alcohol dependent women and men. That experiment will allow
us to test whether low- (N = 30) and high-LR (N = 30) women (50%) and men differ in their stress hormone
response to a binge-like drinking episode, and how those alcohol sensitivity and stress hormone responses
correlate with functional connectivity in the PFC-LHPA network. Data will also be gathered to evaluate
alcohol's stimulating, hedon...

## Key facts

- **NIH application ID:** 10604392
- **Project number:** 5R33AA027634-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ROBERT M ANTHENELLI
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $703,996
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10604392

## Citation

> US National Institutes of Health, RePORTER application 10604392, Exploring Potential Sex Differences In Neurobiological Mechanisms of Alcohol Sensitivity and Tolerance (5R33AA027634-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10604392. Licensed CC0.

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