# PROJECT 3: Neurobiological basis of negative-reinforcement drinking in female and male mice

> **NIH NIH U54** · YALE UNIVERSITY · 2020 · $337,585

## Abstract

The role of Project 3 is to identify and translate the neurobiological mechanisms underlying the ‘dark side
of addiction’ studied across Projects 1 and 2. Women have higher stress reactivity and higher rates of
depressive symptoms than men that may underlie their increased likelihood of chronic drinking. Since women
are particularly sensitive to effects of stress on negative reinforcement drinking (NRD, see Overall Section), a
primary aim of Project 3 is to identify mechanisms related to NRD and related treatments. The amygdala is a
sexually-dimorphic structure essential for stress reactivity, and both norepinephrine (NE) and GABA signaling
are critical for stress-induced behaviors. Based on the established role of GABA and NE in response to both
stress and alcohol use, we hypothesize that the increased susceptibility to chronic alcohol use and relapse in
women is partly due to sex differences in GABA-NE balance in subregions of the amygdala. We have shown
that guanfacine, a NE agonist at α2A receptors, decreases activity of amygdala neurons and induces
anxiolytic and antidepressant-like effects, with sex-dependent patterns of neuronal activation. We therefore
hypothesize that targeting pre- and postsynaptic NE receptors or activating GABA neurons will counteract
NRD, and could have synergistic effects on amygdala neuronal activity and behaviors induced by stress. We
further hypothesize that these neuronal mechanisms interact with neuroinflammatory pathways, such as
microglial activation, to modify synaptic structure in the brain area, and that targeting these neuroadaptations
could alter NRD in a sex-dependent manner. Finally, we know that alcohol metabolism differs in men and
women, and have identified a greater effect of decreased brain metabolism of ethanol in female compared to
male mice. In Project 3, we will 1) determine whether targeting noradrenergic receptors decrease overall
ethanol intake, as well as NRD in female and male mice, 2) determine whether NE manipulations and GABA
neuron activity in the amygdala have synergistic effects on NRD in female and male mice using molecular
genetics to target specific GABAergic circuit mechanisms, 3) determine the effects of noradrenergic receptors
and GABA neuron activity on ethanol-induced microglia alteration and synaptic density in female and male
mice, and 4) identify interactions between brain alcohol metabolism and these signaling pathways in NRD.
These studies will provide mechanistic data relevant for studies in Projects 1 and 2 to identify brain
mechanisms that may modulate stress-related alcohol use in a sex-dependent manner, and to determine how
this contributes to sex differences in alcohol-related behaviors.

## Key facts

- **NIH application ID:** 9854093
- **Project number:** 1U54AA027989-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Marina R Picciotto
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,585
- **Award type:** 1
- **Project period:** 2020-03-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854093

## Citation

> US National Institutes of Health, RePORTER application 9854093, PROJECT 3: Neurobiological basis of negative-reinforcement drinking in female and male mice (1U54AA027989-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854093. Licensed CC0.

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