# Recruitment of striatal enkephalin by cocaine as a substrate for striatopallidal circuit adaptations and cocaine seeking

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $45,771

## Abstract

PROJECT ABSTRACT
40% of patients who are diagnosed with cocaine use disorder are considered to have a severe cocaine use
disorder meeting six or more criteria from the DSM-5. The lack of effective medication for cocaine use disorder
demonstrates an urgent need to better understand the effect of cocaine on neurobiology and behaviors. Cocaine-
induced increase in striatal dopamine release is essential for cocaine reinforcement, however, the mechanisms
of striatal circuit adaptations inducing cocaine seeking is not well established. The overall objective of this
proposal is to determine the mechanism by which cocaine affects striatopallidal circuit activity to facilitate cocaine
seeking and taking. My central hypothesis is that 1) cocaine-induced increases of the opioid peptide, enkephalin
in the striatum suppresses GABA transmission from striatal neurons via δ/µ opioid receptors and, as a result,
disinhibits VP GABA neurons, and 2) striatal enkephalin plays a key role in cocaine seeking.
Aim 1: Determine the necessity of striatal enkephalin in cocaine-induced adaptations in the
striatopallidal circuit: Based on our preliminary data and previous findings, I hypothesize that increase in
enkephalin in the striatum during withdrawal from a history of cocaine exposure leads to suppression of GABA
transmission from enkephalin-expressing striatal neurons, which increases excitability of the postsynaptic VP
GABA neurons. We will test this by performing whole-cell electrophysiology recordings in D2-MSN-selective
enkephalin knockouts with a history of cocaine exposure, and measure GABA transmission from striatal neurons
onto VP GABA neurons and VP neuron excitability. The use of exogenous enkephalin and opioid receptor
selective antagonists will confirm striatal enkephalin and determine the type of opioid receptor as a mechanism
for depression of GABA transmission and increased excitability. Immunohistochemistry will confirm the type of
recorded VP neurons.
Aim 2: Determine the role of striatal enkephalin in cocaine self-administration: Based on our preliminary
data, I hypothesize that striatal enkephalin facilitates self-administration and cocaine seeking. We will test this
by performing operant self-administration using striatal neuron-selective enkephalin knockouts and examine the
effect of striatal enkephalin deletion on cocaine seeking and taking and the motivation for cocaine.
Through completion of this proposal, and under the guidance of my sponsors, Drs. Lauren Dobbs and Robert
Messing, who are experts in substance use disorder research, I will receive extensive training to develop
professional skills, expand my laboratory skillset, and improve my communication skills for post-doctorate
research career in neuroscience. Combined with the training resources and expansive research expertise
available at University of Texas at Austin, I will be well-supported throughout this fellowship and make a
successful transition to a post-doctoral research position...

## Key facts

- **NIH application ID:** 10827113
- **Project number:** 1F31DA058522-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Kanako Matsumura
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,771
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827113

## Citation

> US National Institutes of Health, RePORTER application 10827113, Recruitment of striatal enkephalin by cocaine as a substrate for striatopallidal circuit adaptations and cocaine seeking (1F31DA058522-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10827113. Licensed CC0.

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