# Plasticity of GABA input to VTA dopamine neurons in opioid use disorders

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Despite their dangers, the number of opioid prescriptions written for veterans has increased sharply since
2000, and veterans are more prone than the general population to both suicide and the development of use
disorders following opioid treatment. Target receptors for opioids are widely expressed throughout the brain
and periphery, but their reinforcing properties are largely mediated by their action in mesocorticolimbic areas
such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). In the VTA, activation of
presynaptic mu-opioid receptors is known to blunt release of the inhibitory neurotransmitter GABA, thus
“disinhibiting” dopamine neuron activity. Preliminary work has established that the modulatory peptide
neurotensin can activate presynaptic neurotensin 1 receptors (NtsR1) to enhance GABA release in the VTA.
While this novel form of synaptic plasticity would be expected to directly counteract the effects of opioids, it is
not known how repeated opioid exposure interacts with neurotensin effects on GABA signaling. Opioids and
neurotensin are both known to modulate pain; however, there are significant gaps in our knowledge of how
these compounds interact at the synaptic and circuit level in the VTA to affect drug reinforcement. Improved
treatments for opioid use disorders are desperately needed, both for the general population but also for aging
veterans that will increasingly develop painful conditions that require long-term treatment. The proposed
studies are necessary to determine the feasibility of targeting the neurotensin system to modulate
reinforcement and relapse in individuals that no longer can control their opioid intake.
 We will combine brain slice electrophysiology and cell type-specific molecular techniques with self-
administration of the opioid remifentanil in mice to explore these issues. The use of operant self-administration
in mice offers several key advantages: mice are able to titrate their intake based on individual sensitivity, and
using mice instead of rats opens up the powerful tools of mouse genetics (i.e., Cre-lox technology) to
experimental manipulations. The hypothesis to be tested is that a history of remifentanil self-administration
decreases neurotensin-induced enhancement of GABA release in the NAc  VTA circuit, removing a critical
break on dopamine neuron excitability during drug intake to increase reinforcement. Experiments in Aim 1 will
identify the sensitivity of individual GABA inputs in the VTA to neurotensin, and determine how plasticity is
affected by remifentanil self-administration as well as following a forced abstinence. Experiments in Aim 2 will
use chemogenetics to activate specific GABA inputs to determine their effect on remifentanil self-administration
behavior and cue responding following a forced abstinence. A novel cell type-specific neurotensin receptor
knockout will provide additional information on the role of specific cell types on opioid self-administration.
Expe...

## Key facts

- **NIH application ID:** 10259310
- **Project number:** 1I01BX005396-01A1
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** Michael J Beckstead
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259310

## Citation

> US National Institutes of Health, RePORTER application 10259310, Plasticity of GABA input to VTA dopamine neurons in opioid use disorders (1I01BX005396-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10259310. Licensed CC0.

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