# Mitochondrial signaling dynamics in cocaine use disorder

> **NIH NIH DP1** · RESEARCH TRIANGLE INSTITUTE · 2024 · $663,198

## Abstract

PROJECT SUMMARY
 Cocaine use disorder continues to be a significant health burden, with psychostimulant overdose
deaths rising significantly over the past few years. Cocaine exposure can alter aspects of mitochondrial
function, but the tools to access and manipulate mitochondria in vivo are limited. Mitochondria contribute a
significant amount of the energy required for events in the synapse in the form of adenosine triphosphate
(ATP). Production of ATP in mitochondria near synapses is tightly regulated by the influx of calcium into
mitochondria and leads to the generation of reactive oxygen species within the mitochondrial matrix. The
studies in this proposal aim to measure and manipulate mitochondrial function, specifically calcium and
hydrogen peroxide signaling in vivo, to determine how mitochondrial activity in dopamine neurons is altered in
response to cocaine exposure. We will target three mitochondria-specific protein-encoding genes using a novel
CRISPR viral strategy to knock out genes from dopamine neurons in DATCre mice in vivo. The target genes are
involved in regulating calcium and hydrogen peroxide concentrations in mitochondria: Micu1, which is part of
the mitochondrial calcium uniporter complex and allows mitochondrial calcium influx; Crls1, which encodes an
enzyme necessary for the synthesis of cardiolipin, a mitochondrial phospholipid involved in integrating calcium
and reactive oxygen species signaling; and Sod2, a mitochondria-specific superoxide dismutase that converts
superoxide into hydrogen peroxide and enables removal of ROS from the mitochondrial matrix. Notably, Micu1
and Crls1 encode mitochondrial proteins that have been identified as targets of lead compounds, allowing for a
relatively rapid determination of whether these systems can be modulated in vivo for substance use disorder
treatments. To begin developing drugs for Sod2 and to refine drugs targeting Micu1 and Crls1, these studies
will use mitochondrially-targeted fluorescent sensors for calcium and hydrogen peroxide in combination with
fiber photometry in vivo. My preliminary evidence shows that HyPerRed, a hydrogen peroxide sensor, can be
used in vivo in cortical neurons to record responses to drugs of abuse. The studies in this proposal will expand
on these characterizations and further determine how cocaine may alter reactive oxygen species activity in
presynaptic terminals of dopamine neurons in the nucleus accumbens core. I will also test mitochondrially-
targeted GCaMP to develop a comprehensive understanding of how calcium and reactive oxygen species
activity is coordinated within mitochondria. These sensors will be combined with the CRISPR viral knockout
strategies and pharmacological tools targeting mitochondria to further characterize the specificity of these
signals and the possible impact of these pharmacological approaches on neural function and behavior.
Together, these studies will enable the exploration of a novel avenue of research by monitorin...

## Key facts

- **NIH application ID:** 10903745
- **Project number:** 5DP1DA058362-02
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Antony Daniel Abraham
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $663,198
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903745

## Citation

> US National Institutes of Health, RePORTER application 10903745, Mitochondrial signaling dynamics in cocaine use disorder (5DP1DA058362-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10903745. Licensed CC0.

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