# COCA: Project 4. Neurocircuit Strategy to Decrease Cocaine Cue Reactivity

> **NIH NIH P50** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $318,928

## Abstract

PROJECT SUMMARY – Project 4
In spite of substantial research effort, cocaine dependence is a particularly difficult substance
use disorder to treat. Preclinical models in the Center demonstrate that decreasing neuronal
activity in the ventromedial prefrontal cortex (vmPFC) and ventral striatum (i.e. nucleus
accumbens core), henceforth corticostriatal circuit, block cocaine cue-induced reinstatement.
The scientific and clinical premise of Project 4 is that targeted inhibition of the corticostriatal
circuit will dampen cocaine cue-induced craving in cocaine users. Continuous theta burst
stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation that induces long
term depression-like (LTD-like) decreases in neural excitability in the area stimulated and
downstream monosynaptic targets. A single dose of cTBS to the vmPFC selectively decreases
activity in the ventral striatum and self-reported craving. Recently, we found that N-
acetylcysteine (NAC) increases corticostriatal resting state functional connectivity (rsFC) in
nicotine users concomitant with reducing craving. The overarching goals of Project 4 are to
evaluate the efficacy of combined cTBS+NAC on addiction pathophysiology in corticostriatal
circuitry, and to bidirectionally translate our findings with the preclinical COCA Projects. We
will determine if LTD-like cTBS decreases cocaine cue reactivity in cocaine dependent
individuals (Aim1), and if NAC strengthens corticostriatal rsFC (Aim 2). Then, we will examine
the efficacy of cTBS+NAC to synergistically reduce drug cue reactivity and craving (Aim 3). These
aims will be evaluated through a double blinded (TMS: TBS vs. SHAM; Medication: NAC vs.
Placebo: PBO) study in 96 cocaine dependent individuals. All individuals will undergo an fMRI
baseline scan and then randomized to one of 4 groups: 1) NAC + TBS, 2) NAC + Sham, 3) PBO +
TBS, 4) PBO + Sham). As these data emerge, we will work closely with preclinical Projects 1-3 to
provide these projects with human circuitry data that can help guide their studies. Conversely,
we will receive data regarding corticostriatal mechanisms generated in rodent models of
relapse that can inform the interpretations of our clinical data and guide our research through
greater understanding of the underpinning molecular and circuit level neurobiology.

## Key facts

- **NIH application ID:** 10404587
- **Project number:** 5P50DA046373-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Colleen A Hanlon
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $318,928
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404587

## Citation

> US National Institutes of Health, RePORTER application 10404587, COCA: Project 4. Neurocircuit Strategy to Decrease Cocaine Cue Reactivity (5P50DA046373-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10404587. Licensed CC0.

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