# Pharmacological Characterization of KCC2 as a Target for Cocaine Use Disorder

> **NIH NIH U18** · UNIVERSITY OF PENNSYLVANIA · 2020 · $243,188

## 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. Until recently, cocaine use had been slowly declining, but recent findings indicate a
resurgence in cocaine abuse accompanied by a sharp increase in cocaine-related hospitalizations and deaths.
These facts highlight the need for effective treatments for cocaine use disorder (CUD) because there are
presently no FDA-approved pharmacologic treatments for CUD. The proposed studies of the K+-Cl- cotransporter
KCC2 as a novel therapeutic target to mitigate CUD are timely, highly significant, and appropriately aimed at the
factors underlying heavy cocaine use.
 KCC2 is expressed in the central nervous system, where it uses the outwardly directed K+ gradient
generated by the Na+-K+ ATPase pump to extrude Cl- from neurons. This Cl- extrusion maintains a low intra-
neuronal Cl- concentration required for hyperpolarizing, inhibitory GABAergic currents. Our preliminary results
show that cocaine 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, leads to heavier cocaine self-administration.
Our preliminary results indicate that if we prevent KCC2 downregulation or correct KCC2 function after it has been
downregulated, then we decrease cocaine self-administration.
 In the proposed experiments, we aim to validate KCC2 as a target to mitigate cocaine self-administration.
We will first determine the duration and magnitude of KCC2 functional downregulation by cocaine. Then, we will
directly up and down regulate KCC2 in the brain region of interest to verify that KCC2 changes alone can regulate
cocaine self-administration. Finally, we will establish stable cocaine self-administration in rats and dose-
dependently decrease cocaine consumption with an agonist to KCC2. The research will test a potential
therapeutic drug acting to boost KCC2 function to mitigate the increased cocaine self-administration induced by
cocaine itself.

## Key facts

- **NIH application ID:** 10105506
- **Project number:** 1U18DA052399-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John A. Dani
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $243,188
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-12-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105506

## Citation

> US National Institutes of Health, RePORTER application 10105506, Pharmacological Characterization of KCC2 as a Target for Cocaine Use Disorder (1U18DA052399-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10105506. Licensed CC0.

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