# COCA - Project 3.  Tetrapartite Synapses Regulate Cue-induced Drug Seeking

> **NIH NIH P50** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $232,348

## Abstract

PROJECT SUMMARY – Project 3
Addiction to drugs of abuse produces pathological changes in synaptic physiology that impair the
capacity of the prefrontal cortex (PFC) to communicate with the nucleus accumbens, and impede the
successful regulation of drug seeking. The Center for Opioid and Cocaine Addiction (COCA) studies the
genetic, cellular and physiological mechanisms of relapse in the PFC and nucleus accumbens rodent
models and bidirectionally translates this with COCA clinical studies using fMRI read-out of treatments
with N-acetylcysteine (NAC) and PFC transmagnetic stimulation (TMS) for cue reactivity in cocaine users.
Project 3 specifically explores the nucleus accumbens for synaptic adaptations after heroin and cocaine
self-administration in mice and rats, and the adaptations that occur during cue-induced drug seeking.
We find both enduring changes in withdrawal and transient changes during cue-induced heroin and
cocaine seeking that are correlated with the intensity of the relapse event. These changes are present in
all four compartments of the synapse (pre- and postsynapse, astroglia and extracellular matrix). By
simultaneously examining the 4 synaptic compartments of the tetrapartite synapse, we are accessing
processes heretofore poorly studied in relation to addiction, which may contain unique opportunities for
therapeutic development. Animal & Validation Core B will provide rats and mice trained to self-
administer heroin or cocaine. Our endpoints include cell morphology, cell signaling and physiological
processes. Specifically, we will measure enduring and cue-induced transient changes in the morphology,
synaptic glutamate-mediated currents and protein expression in specific cell types in the accumbens
using transgenic rats and mice and cell-specific viral mediated expression of transgenes in the nucleus
accumbens. Finally, pursuant to an overarching COCA goal to understand which cell type and neuronal
subpopulation is mediating the effects of cue-induced heroin and cocaine seeking, we administer the
treatments used in the clinical Project 4 (NAC and continuous theta burst stimulation) to provide
bidirectional construct validity for the relapse-related discoveries in Project 3.

## Key facts

- **NIH application ID:** 10168499
- **Project number:** 5P50DA046373-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Peter W Kalivas
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $232,348
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168499

## Citation

> US National Institutes of Health, RePORTER application 10168499, COCA - Project 3.  Tetrapartite Synapses Regulate Cue-induced Drug Seeking (5P50DA046373-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10168499. Licensed CC0.

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