# Synapse-specific interactions between ethanol and opioid receptor-mediated synaptic depression in dorsal striatum

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $427,872

## Abstract

Project Summary
There is no doubt that the alcohol use disorders (AUDs) have a significant socioeconomic toll on the United
States and the rest of the world. Many current therapeutics are not sufficiently effective, as they do not target the
neurobehavioral underpinnings contributing to the development and maintenance of alcohol abuse in many
individuals. There is a critical need for novel therapeutic interventions that can undo the negative effects of
ethanol on brain circuitry, restoring cognitive control over drinking behavior. A barrier to progress is a lack of
understanding of the specific effects that ethanol has on select synapses within parts of the brain known to
control alcohol-related behaviors and even the behavioral role of many of these select synapses in the context
of the larger function of each brain region. Our preliminary data indicate that ethanol only affects certain forms
of opioid receptor-mediated synaptic plasticity at very specific synapses within the dorsal striatum while leaving
plasticity at nearby synapses unaffected. One of these synapses is the inputs from the anterior insular cortex
(AIC) to the dorsolateral striatum (DLS). The AIC is involved in ethanol interoception and the DLS controls
habitual responding for ethanol drinking and seeking behavior. In vivo ethanol exposure in mice disrupts mu
opioid long-term synaptic depression (LTD) at this synapse while leaving mu opioid signaling at other synapses
unaffected. LTD mediated by kappa and delta opioid receptors occur at unidentified dorsal striatal synapses and
ethanol could have similar differential effects on these forms of LTD. Our data also show that LTD at AIC-DLS
synapses is likely mediated by altered cAMP signaling and de novo protein synthesis. The objective of this
proposal is to determine synapse-specific opioid LTD mechanisms and how ethanol selectively affects some
synapses, while leaving others unaffected and to determine the behavioral relevance of opioid LTD at AIC-DLS
synapses. Our central hypothesis is that alcohol disrupts dorsal striatal opioid plasticity at specific synapses due
to distinct alcohol-sensitive signaling pathways at synapses that modulate alcohol consumption, seeking, and
interoception. In Aim 1, we will identify the impact of in vivo ethanol exposure on mu, delta, and kappa opioid
receptor-mediated synaptic depression at specific types of dorsal striatal glutamatergic synapses. In Aim 2 we will
determine the mechanisms of ethanol-sensitive and insensitive forms of dorsal striatal opioid plasticity to
decipher the impact of ethanol on these signaling pathways. In Aim 3 we will decipher the role of mu opioid LTD
at AIC-DLS synapses in ethanol consumption, seeking, and interoception. We will use brain slice
electrophysiology, in vitro and in vivo optogenetics, transgenic mice, viral vectors, and pharmacological tools to
address these three aims. By understanding the synapse-specific effects of ethanol on plasticity mechanisms at
b...

## Key facts

- **NIH application ID:** 10240541
- **Project number:** 5R01AA027214-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Brady Atwood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,872
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240541

## Citation

> US National Institutes of Health, RePORTER application 10240541, Synapse-specific interactions between ethanol and opioid receptor-mediated synaptic depression in dorsal striatum (5R01AA027214-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240541. Licensed CC0.

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