# Microglia in Stimulant and Opioid Action

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $240,463

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 3
 Project 3's objective is to address the role of microglia in modulating transcriptional adaptations in nucleus
accumbens (NAc) and dorsal striatum (DS) neurons triggered by cocaine or opioid exposure. Microglia
contribute to normal brain development and function by supporting neuronal survival and removing non-
functional neurons and synapses. We found—with Project 2—that ablation of microglia increases behavioral
responses to cocaine and to opioids, including drug self-administration (SA). These findings support the
hypothesis that microglia may function homeostatically to oppose conditions of excessive dopaminergic
transmission, such as seen with cocaine or opioid exposure. We have found as well that 10-15% of microglia in
striatum, but not other brain regions, express the D1 receptor (D1R), raising the novel possibility of direct
effects of drug (via increased dopaminergic transmission) on microglia, a possibility for which we now have
robust evidence. As next steps, we propose to fully characterize the influence of microglia in controlling neural
and behavioral responses to cocaine and opioids in mouse models. This will include delineating a role for all
microglia in striatum as well as the selective role played by D1R+ microglia and by D1 receptor signaling within
those microglia. We will next characterize the influence of microglia—again D1R+ and D1R- subpopulations—
on the ability of cocaine or opioids to influence gene expression profiles in the major neuronal cell types of NAc
and DS. This work includes characterizing a mechanism involving adenosine signaling that bidirectionally
couples microglia to striatal neuron functioning. As well, we will characterize changes in gene expression
induced by drug exposure in D1R+ and D1R- subpopulations of microglia themselves within striatum. These
experiments are made possible by several novel lines of genetic mutant mice that enable the selective
manipulation of microglial subpopulations within striatum combined with RNAseq of isolated neuronal and
microglia cell types, including at the single cell level. These investigations of cocaine and opioids in mice set
the stage for follow up studies of humans with substance use disorders. Overall, this Project is providing
paradigm-shifting information about the role of microglia in the pathophysiology of drug addiction.

## Key facts

- **NIH application ID:** 10934812
- **Project number:** 2P01DA047233-06A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Anne Schaefer
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $240,463
- **Award type:** 2
- **Project period:** 2019-02-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934812

## Citation

> US National Institutes of Health, RePORTER application 10934812, Microglia in Stimulant and Opioid Action (2P01DA047233-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10934812. Licensed CC0.

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