# N-acetylcysteine Effects on Tetrapartite Synapses in Heroin Seeking

> **NIH NIH F30** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $13,680

## Abstract

PROJECT SUMMARY/ABSTRACT
Opioid addiction is a major public health issue. This, in part, is due to lack of non-opioid based therapeutics.
Following daily heroin use, as well as use of other drugs of abuse, dysregulation in glutamate homeostasis in
nucleus accumbens (NAc) has been observed, which serves as a predisposing factor to relapse. This is a result
of heroin-induced enduring down-regulation and reduced uptake by the astroglial glutamate transporter, GLT-1.
Clinical and preclinical studies utilizing N-acetylcysteine (NAC), an antioxidant that upregulates GLT-1, reveal its
ability to reduce cocaine craving and reinstated heroin seeking, respectively. Reinstatement to heroin-associated
cues is regulated by transient synaptic potentiation (t-SP) in nucleus accumbens core (NAcore), which is
mediated by activity of matrix metalloproteinases (MMPs). However, it is unknown if NAC inhibits MMP activity
in NAcore to inhibit t-SP and heroin reinstatement. Hence, this proposal outlines a series of experiments that will
determine if NAC inhibition of t-SP and reinstated heroin seeking involves MMP activity and if this is cell-type
specific. My preliminary data indicates decreased MMP activity (quantified as integrated density) after 15 minutes
of cue-induced heroin reinstatement in NAC-treated rats (100 mg/kg daily X 5 days) compared to saline-treated
rats. I hypothesize that NAC will suppress MMP activity in NAcore during cued-reinstatement and this will be
GLT-1 dependent. I further hypothesize NAC suppresses MMP-9 activity selectively around D1 MSNs during
reinstatement and enhances MMP-2 activity adjacent to D2 MSNs during extinction. These hypotheses, based
upon preliminary data, will be tested through two specific aims. Aim 1 will employ in vivo zymography and GLT-
1 anti-sense morpholino strategies to assess NAC’s effects on MMP activity during cued heroin reinstatement.
Aim 2 will employ cell-specific viral transfection of D1 or D2 medium spiny neurons (MSNs) in NAcore to assess
whether NAC treatment effects MMP activity selectively around D1 or D2 MSNs under extinguished and
reinstated conditions. In addition to understanding MMP signaling and NAC’s ability to inhibit cued reinstatement,
this fellowship will train me in cutting-edge techniques for analyzing synaptic events underlying addiction.

## Key facts

- **NIH application ID:** 9978797
- **Project number:** 5F30DA046143-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Vivian Chioma
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $13,680
- **Award type:** 5
- **Project period:** 2018-08-01 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978797

## Citation

> US National Institutes of Health, RePORTER application 9978797, N-acetylcysteine Effects on Tetrapartite Synapses in Heroin Seeking (5F30DA046143-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978797. Licensed CC0.

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