# Dissecting the functional relevance of unique subpopulations of striatal dopamine receptors in opioid use disorder

> **NIH NIH R36** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $53,999

## Abstract

PROJECT SUMMARY
The opioid epidemic has skyrocketed in the United States. Despite the enormous public health impact, the basic
mechanisms underlying the development of opioid use disorder (OUD) remain unclear. Striatal dopamine (DA)
neurotransmission is critical for opioid reward-related behaviors. The nucleus accumbens (NAc) region within
ventral striatum serves as a crucial node for opioid-conditioned reinforcement via dopamine receptor signaling.
Furthermore, the medial shell of the NAc (mNAcSh) has increasingly been implicated in opioid reinforcement
behavior in a mouse self-administration model. Opioids enhance DA release from midbrain DA neurons, whose
projections converge with glutamatergic input in the NAc. 95% of the NAc neuronal population consists of
GABAergic medium spiny neurons (MSNs) are largely segregated into two populations based on expression of
DA D1 (D1R) versus D2 (D2R) receptors. Indeed, D1R+ and D2R+ MSNs project to different output structures in
the basal ganglia circuitry which have opposite effects on motor control: D1R+ MSNs exert stimulatory effects on
movement via the direct pathway whereas D2R+ MSNs exert inhibitory control over movement via the indirect
pathway. Moreover, the DA receptors expressed by D1R+ versus D2R+ MSNs are coupled to different G proteins
which signal via different intracellular pathways. In the context of opioids, morphine differentially acts on D1R+
versus D2R+ NAc MSNs. Specifically: 1) morphine administration increases glutamatergic synaptic strength in
NAc D1R+ MSNs, while D2R+ MSNs show opposite effects; and 2) morphine exposure preferentially generates
silent synapses in NAc D2R+ MSNs compared to D1R+ MSNs. Anatomic and functional evidence suggests that
the composition of striatal D1R+ and D2R+ MSN populations is more heterogenous than previously thought. Until
recently, the inability to selectively target D1/2R-co-expressing MSNs has made it very difficult to dissect the
respective contributions of these co-expressing MSNs given their close proximity in the striatum. As a result,
most studies have been in vitro and relied on ectopic receptor overexpression, leading to conflicting findings and
unclear relevance in vivo. Moreover, the specific roles of D1/2R-co-expressing MSNs in opioid abuse have yet
to be examined. To address this, we developed tools to dissect the functional and anatomical properties of
different MSN subpopulations within the same brain. This includes use of the intersectional genetic
INTRSECT2.0 system, which allows us to label and manipulate subsets of MSNs expressing D1R or D2R alone
versus those co-expressing D1R and D2R with great temporal and spatial specificity. With these tools, we will
determine if D1/2R-co-expressing MSNs represent a distinct MSN population, different from neurons that only
express D1R or D2R. We hypothesize that D1/2R-co-expressing NAc MSNs have unique anatomic, physiologic,
and behavioral functions critical for opioid actions. To address thi...

## Key facts

- **NIH application ID:** 10934372
- **Project number:** 5R36DA057972-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jenesis Kozel
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,999
- **Award type:** 5
- **Project period:** 2023-09-30 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934372

## Citation

> US National Institutes of Health, RePORTER application 10934372, Dissecting the functional relevance of unique subpopulations of striatal dopamine receptors in opioid use disorder (5R36DA057972-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10934372. Licensed CC0.

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