# Nitrergic interneurons and cue-induced cocaine seeking

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $339,657

## Abstract

PROJECT SUMMARY
Vulnerability to relapse remains a significant clinical hurdle in the treatment of addiction. Data from operant
rodent models of addiction and relapse indicate that cocaine-conditioned cue exposure evokes a pronounced
glutamate release in the nucleus accumbens core (NAcore). Cued glutamate release engages a cell type-specific
transient synaptic potentiation in NAcore medium spiny neurons (MSNs), which does not occur during cued
sucrose seeking. This transient synaptic potentiation consists of increased synaptic and structural plasticity in
MSNs. Importantly, the magnitude of this plasticity positively correlates with relapse behavior. We posit that both
the structural component (dendritic spine head expansion) and the synaptic component (increased insertion of
glutamate receptors) of this plasticity are engaged by nitric oxide (NO); a gaseous transmitter produced by
interneurons that express neuronal nitric oxide synthase (nNOS). Consistent with a role for these neurons in
cued relapse, we have recently demonstrated that elevated NO release in the NAcore also occurs in parallel with
glutamate release during cued cocaine seeking. The objectives of the proposed study are to reveal the inputs to
the NAcore required for NO release during relapse, to determine which receptors on NAcore nNOS neurons
regulate NO release and cued cocaine seeking, and to reveal how nNOS participates in the induction of the
transient structural and synaptic plasticity in MSNs that drives cued cocaine seeking. In Aim 1, we will use
chemogenetic inhibition of inputs to the NAcore while recording glutamate and NO release during cued cocaine
seeking. We predict that inputs to the NAcore carrying discreet aspects of cue and contextual salience will
differentially regulate NO release and cued relapse. In Aim 2, we will elucidate how glutamate and dopamine
receptors, specifically expressed on NAcore nNOS interneurons, act in concert to regulate NO production and if
they are required for cued cocaine seeking. To do this we will use transgenic mice that express Cre in nNOS
neurons, Cre-dependent shRNA viral vectors, as well as cocaine self-administration and cued cocaine seeking
trials. We predict that glutamate and dopamine receptor systems in nNOS neurons cooperatively regulate NO
release and cued cocaine seeking. In Aim 3, we will determine if loss of nNOS in the NAcore will prevent cue-
mediated synaptic and structural plasticity in MSNs. To do this we will use an shRNA vector to knockdown nNOS
and concomitant viral labeling of D1 or D2 receptor expressing MSNs in the NAcore. This will be done using
separate cohorts of D1-and D2-promoter driven Cre rats. In Aim 3, we will measure morphological and
electrophysiological readouts synaptic plasticity induced by cues. We expect that loss of nNOS will prevent both
forms of plasticity linked to relapse, predominantly in D1 MSNs. In conclusion, findings from these investigations
will reveal the mechanistic aspects of ho...

## Key facts

- **NIH application ID:** 10457010
- **Project number:** 5R01DA054154-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Michael David Scofield
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,657
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457010

## Citation

> US National Institutes of Health, RePORTER application 10457010, Nitrergic interneurons and cue-induced cocaine seeking (5R01DA054154-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457010. Licensed CC0.

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