# Inhibitory synaptic transmission, stress, and drugs of abuse

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $442,084

## Abstract

Relapse is a central problem associated with the treatment of drug addiction. Exposure to brief stress can
enhance craving and trigger relapse in humans, and triggers robust relapse to drug-seeking behavior in animal
models. Recent work over the past ten years from our lab and others' has shown that a single exposure to an
addictive drug can either initiate or block forms of synaptic plasticity in the ventral tegmental area (VTA), a
region known to be critical in relapse to drug-seeking. We found that brief acute stress blocks synaptic
plasticity at GABAergic synapses on VTA dopamine neurons (LTPGABA), and have characterized the molecular
cascades involved. A single stressful experience activates kappa opioid receptors (κORs), and we showed that
interrupting kappa receptor signaling rescues the LTP in brain slice recordings - but also importantly, prevents
stress-induced reinstatement of drug-seeking. We have recently found that interrupting κOR signaling even
days after the stressor both rescues LTP in dopamine neurons in vitro and prevents reinstatement of drug
seeking in behavioral tests. While all the mechanistic steps are not yet known, all of our data support the
general idea that removal of this normal brake on VTA dopamine neurons contributes to reinstatement. In this
application, we will identify the circuits involved, asking: 1) which GABAergic afferents normally exhibit LTPGABA
and lose it after acute stress, and 2) which dynorphin-releasing afferents and κORs are active during acute
stress and alter the VTA circuit to drive relapse behavior. Knowing the brain regions and specific pathways
involved offers the opportunity to manipulate these towards therapy development.

## Key facts

- **NIH application ID:** 10612377
- **Project number:** 5R01DA011289-23
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Julie A. Kauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $442,084
- **Award type:** 5
- **Project period:** 1997-07-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10612377

## Citation

> US National Institutes of Health, RePORTER application 10612377, Inhibitory synaptic transmission, stress, and drugs of abuse (5R01DA011289-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10612377. Licensed CC0.

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