# Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration

> **NIH NIH R37** · UNIVERSITY OF PENNSYLVANIA · 2021 · $527,837

## Abstract

Project Summary.
 Cocaine is the most widely abused psychostimulant by a wide margin, and it remains a major public
health problem in the US. Cocaine use was slowly declining, but in recent years there has been a resurgence in
cocaine abuse accompanied by a sharp increase in cocaine-related hospitalizations and deaths. These facts
highlight the need for effective medications for cocaine use disorder (CUD) because there are presently no FDA-
approved pharmacologic treatments for CUD. Our exciting preliminary results highlight a novel molecular
substrate that could be targeted to attenuate or prevent cocaine taking and seeking. Specifically, we show that
cocaine exposure alters the expression of KCC2, a K+-Cl- cotransporter that defines the Cl- gradient in midbrain
GABA neurons. Importantly, this cocaine-induced neuroadaptation is associated with circuitry changes in
midbrain GABA neurons that promote and elevate further cocaine taking. These findings support the working
hypothesis that initial cocaine taking alters midbrain GABAergic circuitry and increases the vulnerability for
increased cocaine consumption over time. Thus, KCC2 represents a potential therapeutic target to treat CUD.
 KCC2 is expressed primarily in the central nervous system, and it is amenable to therapeutic manipulation
in humans. KCC2 is highly attractive as a therapeutic target because it is usually constitutively highly active.
Therefore, when normal subjects are treated with KCC2 activators, KCC2 activity is already high, such that
attempts to increase its activity further do not produce deleterious side effects. Under normal physiological
conditions, KCC2 maintains a low intra-neuronal Cl- concentration required for hyperpolarizing, inhibitory
GABAergic currents. Our preliminary results indicate that cocaine dose-dependently downregulates KCC2 function
in midbrain GABA neurons, thereby altering midbrain GABAergic circuitry. As a consequence of these circuitry
changes, downregulation of KCC2 leads to increased cocaine self-administration. That is, cocaine use itself, by
downregulating KCC2, perpetuates heavy cocaine self-administration. Our preliminary results indicate that if we
prevent KCC2 downregulation or correct KCC2 function, then we decrease cocaine self-administration.
 The overall goal of this proposal is to characterize the functional state of the midbrain GABAergic circuitry
and the disposition of KCC2 function during cocaine self-administration, extinction, and the reinstatement of
cocaine seeking (Aims1 & 2). At each phase of the addiction cycle, we will determine the functional state of the
midbrain GABAergic circuitry as a causal contributor to cocaine taking or seeking. Finally, we will apply two
mechanistically different pharmacotherapies to boost KCC2 function to decrease cocaine self-administration and
cocaine-seeking behavior during abstinence (Aim3). These translationally-relevant studies will test potential
therapeutic drugs acting to boost KCC2 funct...

## Key facts

- **NIH application ID:** 10183525
- **Project number:** 1R37DA053296-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John A. Dani
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $527,837
- **Award type:** 1
- **Project period:** 2021-05-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183525

## Citation

> US National Institutes of Health, RePORTER application 10183525, Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration (1R37DA053296-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10183525. Licensed CC0.

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