# Role of Microglia in Cocaine Actions

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $266,962

## Abstract

PROJECT SUMMARY/ABSTRACT– PROJECT 3
 Project 3's objective is to address the role of microglia in modulating transcriptional adaptations in striatal
medium spiny neurons (MSNs) triggered by cocaine self-administration. Microglia contribute to normal brain
development and function by supporting neuronal survival and removing non-functional neurons and synapses.
We have found that ablation of microglia causes a robust increase in behavioral responses to cocaine or to a
D1 dopamine receptor agonist as well as an increase in dendritic spine density on MSNs. These findings
suggest the hypothesis that microglia may function homeostatically to oppose conditions of excessive
dopaminergic transmission, such as seen with cocaine exposure. We also have found that 10-15% of microglia
in striatum, but not other brain regions, express the D1 receptor, raising the novel possibility of direct effects of
cocaine (via increased dopaminergic transmission) on microglia. We now propose to fully characterize the
influence of microglia in controlling behavioral responses to cocaine in self-administration models. This will
include delineating a role for all microglia in striatum as well as a possible selective role played by D1+
microglia and by D1 receptor signaling within those microglia. We will next characterize the influence of
microglia—again D1+ and D1- subpopulations—on the ability of cocaine self-administration to influence gene
expression profiles in the D1-type and D2-type MSNs of striatum, separately examining nucleus accumbens
and dorsal striatum. We will also characterize the changes in gene expression induced by cocaine self-
administration in D1+ and D1- 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 RNA-seq of isolated neuronal and microglia cell
types—and even at the single cell level. These investigations of cocaine set the stage for follow up studies of
microglia in opiate action as well as in humans with substance use disorders. Overall, the proposal has the
potential to provide paradigm-shifting information about the role of microglia in the pathophysiology of drug
addiction.

## Key facts

- **NIH application ID:** 9864077
- **Project number:** 5P01DA047233-02
- **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:** 2020
- **Award amount:** $266,962
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864077

## Citation

> US National Institutes of Health, RePORTER application 9864077, Role of Microglia in Cocaine Actions (5P01DA047233-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9864077. Licensed CC0.

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