# Dysregulation of midbrain GABAergic circuitry contributes to the motivational properties of cocaine

> **NIH NIH K01** · GEORGETOWN UNIVERSITY · 2023 · $159,301

## Abstract

Cocaine addiction remains a major public health problem in the US, but effective treatments are still
lacking. Cocaine use disorder is characterized by the development of pathological motivation for cocaine,
characterized by intake in the face of rising costs and harmful consequences. Decreasing excessive
motivational importance of drug taking without altering motivation for natural rewards is among the major goals
of treating cocaine addiction. However, development of new pharmacotherapies requires understanding the
basic brain mechanisms underlying cocaine addiction. Identifying these mechanisms is timely because cocaine
use and overdoses have been increasing over the last several years.
A growing body of evidence indicates that midbrain circuits play a critical role in cocaine-related
behaviors. My preliminary data in rodents indicate that cocaine, but not sucrose, dysregulates midbrain
inhibitory circuitry via decreased function of anion transporter, KCC2, located in VTA GABA neurons. This form
of cocaine-induced neuroadaptation in GABAergic signaling has not been described previously, and I plan to
investigate its impact on cocaine self-administration in rats. Given my preliminary findings suggesting that
KCC2 dysfunction contributes to motivational properties of cocaine, I will measure motivation for cocaine self-
administration while manipulating KCC2 activity in the VTA. At the cellular level, KCC2 dysfunction attenuates
GABAA receptor-mediated inhibition leading to hyperexcitability of VTA GABA neurons. To assess the role of
VTA GABA neurons in cocaine motivation, I will use chemogenetic approach in transgenic rat model to directly
manipulate neuronal activity during cocaine self-administration. Ultimately, I will test if cocaine dysregulates
GABAergic signaling in a circuit-specific manner. Accumulated evidence indicates that VTA GABA neurons
project to multiple brain areas and I will focus on GABAergic projection to the nucleus accumbens, a brain
region critically involved in motivational properties of addictive drugs. I will label specific VTA GABA projections
to the medial and lateral shell of the nucleus accumbens and test the effect of cocaine on GABAergic signaling
in these projections. Taken together, the research will illuminate the role of midbrain GABAergic circuitry in the
pathological motivation for cocaine.

## Key facts

- **NIH application ID:** 10611966
- **Project number:** 5K01DA048134-05
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Alexey Ostroumov
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $159,301
- **Award type:** 5
- **Project period:** 2019-06-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10611966

## Citation

> US National Institutes of Health, RePORTER application 10611966, Dysregulation of midbrain GABAergic circuitry contributes to the motivational properties of cocaine (5K01DA048134-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10611966. Licensed CC0.

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