# Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure

> **NIH NIH R00** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2021 · $248,624

## Abstract

Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure
 Chronic ethanol exposure causes pathological changes in behavior, including alterations in cognition
and a transition from flexible, goal-directed alcohol use to inflexible, habitual alcohol seeking. The dorsal
striatum, which is responsible for motor activity, action learning, and habit formation, undergoes changes in
synaptic modulation in response to chronic alcohol exposure. Inhibition of excitatory transmission by
presynaptic G protein-coupled receptors (GPCRs) such as metabotropic glutamate receptor 2 (mGlu2) that
couple to Gi/o proteins is impaired by chronic alcohol. I will explore how alcohol changes GPCR modulation of
specific synapses, and relate these alterations to behavioral adaptations. My central hypothesis is that
reductions in presynaptic GPCR function following chronic alcohol exposure disrupt normal cortical regulation
of striatal function such that dorsolateral striatum-dependent learning is facilitated. Results of the following
studies will provide insight into the therapeutic utility of targeting presynaptic GPCRs such as mGlu2 for AUDs.
Aim 1. Determine the input-specificity of the disruption of mGlu2-mediated modulation of glutamatergic
synaptic transmission in the dorsal striatum. I will use slice electrophysiology and optogenetic techniques
to identify specific excitatory projections to the dorsal striatum that are impacted by chronic alcohol exposure.
Aim 2. Evaluate the effect of alcohol-induced changes in corticostriatal Gi/o-coupled GPCR function on
dorsal striatum-mediated learning. I will use an innovative, genetically-encoded, toxin-based technique to
test the hypothesis that disruption of presynaptic GPCR function in corticostriatal circuits mimics the enhancing
effect of chronic alcohol exposure on dorsal striatum-dependent learning. I will also test the hypothesis that
activation of presynaptic Gi/o-coupled Designer Receptors Exclusively Activated by Designer Drugs
(DREADDs) in corticostriatal circuits will reverse alcohol-induced enhancement of striatum-dependent learning.
Aim 3. Assess the impact of presynaptic corticostriatal inhibition by Gi/o-coupled GPCRs on habitual
alcohol seeking. I will use pharmacological and chemogenetic strategies to study effects of presynaptic
GPCR activation (mGlu2 or DREADD) on habitual alcohol seeking.
Training: I will gain extensive experience with models of chronic alcohol exposure, including chronic
intermittent ethanol vapor exposure (CIE) (Aims 1 and 2) and operant ethanol self-administration (Aim 3). I will
also learn sophisticated models of instrumental learning to look at alcohol-induced changes in cognition (Aim
2) and habitual alcohol seeking behavior (Aim 3). Training in behavioral assays will allow me to apply my
interest in GPCR modulation of synaptic transmission to unanswered questions about how synaptic modulation
influences animal behavior. I will also receive career de...

## Key facts

- **NIH application ID:** 10241461
- **Project number:** 5R00AA025403-04
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Kari Johnson
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,624
- **Award type:** 5
- **Project period:** 2017-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241461

## Citation

> US National Institutes of Health, RePORTER application 10241461, Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure (5R00AA025403-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241461. Licensed CC0.

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