# Functional consequences of cocaine self-administration on astrocytes

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $402,350

## Abstract

Project Summary/Abstract
Accumulating evidence has identified nucleus accumbens astrocytes as salient targets of drug abuse. For
example, numerous studies indicate that rat self-administration of multiple drug classes results in impaired
glutamate homeostasis, as well as decreased structural features and synaptic colocalization of nucleus
accumbens astrocytes. Preliminary data for this proposal reveal that male rat accumbens astrocytes exhibit
striking (~40%) reductions in surface area, volume, and synaptic colocalization 45 days after 10 days of long-
access (6h/d) cocaine self-administration. These findings suggest loss of physiological function of astrocytes
as regulators of neural circuits. However, the mechanism(s) driving these observations are unknown, as are
the consequences to neural function. We hypothesize that astrocyte pathology underscores the neural
adaptations and increased measures of craving observed across prolonged abstinence (also known as
incubation). Accordingly, the goal of this proposal is to define the relationship between cocaine self-
administration and the onset of astrocyte dysfunction in the nucleus accumbens, as well as the relationship
between astrocyte dysfunction, synaptic transmission, and behavior. Aim 1 will assess the effects of operant
cocaine self-administration on evoked Ca2+ responses in accumbens astrocytes as a function of both self-
administration and abstinence, and will determine the functional significance of astrocyte Ca2+ to cocaine
seeking behaviors. Aim 2 will examine how cocaine self-administration affects the ability of astrocytes to
negatively regulate excitatory synaptic transmission in D1 and D2 receptor-positive medium spiny neurons.
Lastly, Aim 3 will establish the role of dopamine and G protein-mediated astrocyte signaling in the pathological
effects of cocaine on accumbens astrocyte structure. For each aim, we will evaluate endpoints as a function of
time across abstinence. These objectives will collectively be accomplished by leveraging a multimodal
approach that spans cellular physiology to circuit analysis and animal behavior, combining rat cocaine self-
administration with high-resolution imaging of fluorescently-labeled astrocytes, acute slice imaging of Ca2+-
labeled astrocytes using a photoconvertible Ca2+ indicator (astro-CaMPARI2), astrocyte DREADD stimulation,
astrocyte Ca2+ depletion using an astrocyte-expressed PMCA2 Ca2+ pump, whole cell patch-clamp
electrophysiology, neuronal subtype-specific analyses using Drd1a-Cre and Drd2-Cre transgenic rats, and
fluorescent imaging of an adenosine biosensor GRABAdo. Collectively, these studies will define the relationship
between astrocyte dysfunction across abstinence from cocaine self-administration with neural physiology and
behavior.

## Key facts

- **NIH application ID:** 10832649
- **Project number:** 5R01DA057776-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Kathryn Joanna Reissner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,350
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832649

## Citation

> US National Institutes of Health, RePORTER application 10832649, Functional consequences of cocaine self-administration on astrocytes (5R01DA057776-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10832649. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*