# Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $361,097

## Abstract

Project Summary:
 Clear neuroadaptations occur as a result of alcohol use disorders, underlying the debilitating health
risks and social problems associated with the disease. While changes in GABAergic, glutamatergic and
dopaminergic neurotransmission are strongly implicated, the precise neurological mechanisms that cause
enhanced susceptibility of alcohol intake and preference are not yet well understood. As a result, current
treatments available to combat alcoholism are sparse and nonspecific— besides psychotherapy, detoxification
and nausea-inducing, emetic drugs, there are no pharmacological targets for treating the disease. Recent
studies have uncovered non-canonical GABA synthesis mediated by aldehyde dehydrogenase 1a1
(ALDH1a1) and co-release from dopaminergic midbrain neurons, and we have gathered strong evidence
suggesting that this alternative GABA synthesis pathway is diminished with blood alcohol levels that are
associated with binge drinking. Methodological advances now provide the opportunity to directly examine and
dissect the role of this GABA pathway in acute and chronic alcohol exposure. In this proposal, we hypothesize
that the balance between co-released dopamine and GABA by midbrain dopamine neurons is critical for
postsynaptic striatal spiny projection neurons (SPNs). In addition, alcohol and/or its metabolic product inhibit
dopaminergic GABA by impairing GABA non-canonical synthesis, ultimately perturbing the co-released GABA
by dopamine neurons in the dorsal striatum, and lead to enhancement in susceptibility of alcohol intake and
preference. We will employ the use of genetically modified mice and virus injections to directly examine
dopamine neurons and the specific pathways involved in GABA synthesis, modulation and release. By
optogenetic activation of dopamine terminals in the striatum and whole-cell patch clamp on identified principle
striatal cells, our experiments will provide a high-resolution assessment of the function of dopaminergic
GABAergic in normal and enhanced alcohol intake and preference conditions. Combined with imaging,
electrophysiology, optogenetics, biochemistry and behavioral analysis, this proposal provides a unique, multi-
faceted approach to study dopamine and GABA co-release in the basal ganglia, and the mechanisms by which
chronic binge drinking alters this form of neurotransmitter release.
 Based on our compelling preliminary findings, we aim to 1) examine whether cell-type specific deletion
of ALDH1a1 in dopamine neurons leads to enhanced alcohol preference; 2) pinpoint the mechanism
underlying the inhibition of co-released GABA by alcohol; and 3) investigate alcohol modulation of functional
interplay between GABA and dopamine in the striatum. Our novel initial findings and the studies proposed in
this grant will close the gaps in our knowledge about GABA synthesis in dopaminergic neurons and create a
new window into our understanding of synaptic mechanisms underlying enhanced alcohol intake ...

## Key facts

- **NIH application ID:** 10172801
- **Project number:** 5R01AA025721-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jun Ding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $361,097
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172801

## Citation

> US National Institutes of Health, RePORTER application 10172801, Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons (5R01AA025721-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10172801. Licensed CC0.

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