# Nucleus accumbens cholinergic interneurons and cue-induced cocaine craving

> **NIH NIH K99** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $185,347

## Abstract

Project Summary
A major problem for persons suffering from addiction is persistent vulnerability to relapse, even after long periods
of abstinence. In the `incubation of cocaine craving' model of relapse, rats self-administer cocaine using a Long
Access procedure, and then experience a prolonged abstinence period. During abstinence, rats exhibit a
progressive intensification (incubation) of cue-induced cocaine craving. Plasticity involving medium spiny
neurons in the nucleus accumbens core (NAcc) is required for the expression of `incubated' cue-induced craving.
However, to date no incubation studies have focused on another cell type in the NAcc, the Cholinergic
Interneuron (CIN). CINs make up only 1-2% of NAcc neurons, but are critically involved in learning, memory,
and motivated behaviors. CINs are tonically active, and considerable work now supports the idea that a reduction
in their activity augments motivated behavior. Other work has shown that dopamine D2 receptors (D2-R) on CINs
reduce CIN activity and this correlates with greater motivated behavior; furthermore, D2-R are upregulated in
NAc following cocaine self-administration (SA). Finally, striatal CINs are unique in exhibiting steady-state
activation of the Integrated Stress Response (ISR) pathway, linked to their tonic firing. The ISR maintains cellular
homeostasis by regulating protein translation. In other cell types, the level of ISR activity regulates motivation for
cocaine. This has not been tested for CINs, but the ISR does affect D2-R signaling in these neurons. Integrating
these findings, the over-arching hypothesis to be tested here is that cocaine SA and a subsequent abstinence
period leads to increased D2-R expression on NAcc CINs. This leads to a potentiated inhibition of CINs in
response to DA released during cue presentation, increasing cocaine seeking and leading to reduced ISR activity
and translational reprogramming in CINs. Together these changes contribute to increased motivation for
cocaine-paired cues. To test this hypothesis, transgenic rats and Cre-driven viruses will be used to selectively
monitor and manipulate NAcc CINs. Aim 1 will use fiber photometry to determine the effect of cocaine SA and
an abstinence period on the Ca2+ response (a proxy for activity) to a cocaine-paired cue in CINs, and how D2-R
regulate this response. Recordings will be performed during cue-induced seeking tests on withdrawal day (WD)
1, prior to incubation, and WD40 (after incubation). Aim 2 will determine the role that CINs play in the expression
of `incubated' seeking, through bidirectionally manipulating CINs via chemogenetics prior to WD1 or WD40
seeking tests. Aim 3 will explore how incubation of cocaine craving changes protein translation in CINs, using
cell type specific translating ribosome affinity purification to identify active translating mRNAs (including mRNAs
for the D2-R and markers of ISR activity) and a new viral tool (SPOTlight) to measure ISR activity. While this
...

## Key facts

- **NIH application ID:** 10867450
- **Project number:** 5K99DA057360-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alexander Borg Kawa
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,347
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867450

## Citation

> US National Institutes of Health, RePORTER application 10867450, Nucleus accumbens cholinergic interneurons and cue-induced cocaine craving (5K99DA057360-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10867450. Licensed CC0.

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