# Microglial pruning of dopamine receptors and opioid abuse.

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $388,219

## Abstract

The dopaminergic “reward” circuitry undergoes significant developmental plasticity during
adolescence, including the refinement of dopamine D1 and D2 (D1/D2r) receptors within the
nucleus accumbens (NAc). We have recently demonstrated in male rats that microglia – the
primary immune cells of the CNS that also play a role in sculpting developing circuits – engulf and
eliminate D1rs during a precise window of adolescent NAc development in response to receptor
“tagging” by complement protein C3; and that this developmental pruning of D1rs by microglia is
critical for the development of normal reward-driven behavior (social play). Moreover, rats that
receive repeated morphine during adolescence (but not young adulthood) show persistent
changes in microglial function and increased reinstatement to morphine as adults; and, pre-
treatment with a glial modulator during adolescent morphine exposure prevents this increased
reinstatement, implicating a critical role for microglia. Microglia refine synapses based on
changes in neural activity, leading us to hypothesize that, in males (1) microglia sculpt NAc D1rs
during normal adolescence as a consequence of altered dopamine (DA) activity which leads to
receptor tagging by the “eat me” signal C3; and (2) factors that significantly impact DA signaling
within the NAc during adolescence could persistently alter reward processing - including addiction
liability - by changing microglial pruning of D1rs. We will use 3 aims to test the hypothesis that
dopaminergic input to the NAc leads to complement C3 “tagging” of D1r and phagocytosis by
microglia and that disruptions of this normal input (e.g. by social isolation stress) will lead to
dysregulated long-term reward-driven behaviors. Importantly, D1r refinement occurs via
unknown mechanisms in females, independent of microglia-C3 interaction, and the implications
for addiction have not been assessed. To explore putative mechanisms in females we will
additionally assess changes in D2r, and examine additional putative molecular tags/ “eat-me”
signals.

## Key facts

- **NIH application ID:** 10388826
- **Project number:** 1R01DA055414-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Staci D Bilbo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,219
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388826

## Citation

> US National Institutes of Health, RePORTER application 10388826, Microglial pruning of dopamine receptors and opioid abuse. (1R01DA055414-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10388826. Licensed CC0.

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