# Glutamate, nitrergic interneurons, and cue-induced cocaine seeking

> **NIH NIH F32** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $20,225

## Abstract

PROJECT SUMMARY
Substance Use Disorder (SUD) remains one of the most difficult to treat of all neuropsychiatric disorders, largely
due to the high propensity for relapse, even after prolonged periods of abstinence, owing to craving following re-
exposure of addicts to drug-conditioned stimuli. Cocaine-addicted patients, in particular, maintain relatively high
relapse rates; yet effective treatments for relapse in clinical populations remain elusive. Accordingly, the need
for a better understanding of the biology underlying cue-induced relapse remains critical for designing effective
treatments for addiction. Clinical neuroimaging experiments show heightened activation of cortical and
downstream limbic regions, including the prefrontal cortex, amygdala, and nucleus accumbens, in addicts
exposed to cocaine-conditioned cues (i.e. paraphernalia). Cocaine self-administration studies in rats reveal that
heightened glutamate transmission in the nucleus accumbens core (NAcore), and the subsequent activation of
a sparse population of neuronal nitric oxide synthase (nNOS)-expressing interneurons, regulates cue-induced
craving for cocaine. However, simultaneous, near real time, measurements of glutamate and nitric oxide (NO)
concentrations in the NAcore during cue-induced cocaine seeking has not been performed. Moreover, it is
unknown what glutamate inputs, and what glutamate receptors on nNOS interneurons, are required for cue-
induced NO release. The major goal of this proposal is to disentangle the glutamate inputs to the NAcore, and
glutamate receptor subtypes on nNOS interneurons, required for cue-induced increases in extracellular
glutamate and NO in the NAcore, respectively. This will be addressed using the state-of-the-art techniques
described herein. This goal will be addressed through two specific aims. The first aim is to determine whether
cue-induced activation of prelimbic (PL) cortical (Aim 1a) or basolateral amygdala (BLA, Aim 1b) neurons
projecting to the NAcore is required for cue-induced glutamate release, subsequent NO release, and seeking.
To address this aim, we will use a biosensor-based recording strategy in freely moving rats; allowing for near
real time detection of glutamate and NO levels in the NAcore during cue-induced reinstatement. This will be
combined with transient inhibition of these two glutamate inputs to the NAcore to examine the relative contribution
of each to cue-induced glutamate and NO release. The second aim will be to determine whether mGluR5 (Aim
2a) or GluN2B (Aim 2b) receptors on nNOS interneurons mediates cue-induced NO release in the NAcore and
cocaine seeking. This aim will be addressed using the same recording strategy described above combined with
Cre-dependent viral vectors driving shRNA against these two receptors in male and female mice expressing
temporally regulated nuclear Cre in nNOS interneurons. These studies will fill a critical role in our understanding
of the neurochemical mechanisms underlying...

## Key facts

- **NIH application ID:** 10129882
- **Project number:** 5F32DA050427-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Benjamin Michael Siemsen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $20,225
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-07-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129882

## Citation

> US National Institutes of Health, RePORTER application 10129882, Glutamate, nitrergic interneurons, and cue-induced cocaine seeking (5F32DA050427-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129882. Licensed CC0.

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