# New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers

> **NIH NIH U18** · NORTHEASTERN UNIVERSITY · 2020 · $96,867

## Abstract

PROJECT SUMMARY/ABSTRACT
Cocaine abuse has reached epidemic levels in North America. By 2018, over 5.5 million Americans over the age
of 12 had used cocaine within the past year, and almost 1 million meet DSM-IV criteria for addiction. Overdose
related deaths have more than doubled from 2007 to 2019, reaching almost 16,000 deaths in 2019. Currently,
there are no FDA approved medications available for treating cocaine use disorders. About 24% of those seeking
treatment will relapse within a year following treatment. Relapse rates in abstinent patients are high, because
the currently available treatment regimens do not adequately address addiction. Chronic cocaine abuse leads to
lasting adaptations in the limbic, motivational, and executive areas of the brain. Glutamate homeostasis is
altered, and results in changes in receptor expression in the ventral tegmental area (VTA) and changes in
signaling into the VTA and prefrontal cortex (PFC); relapse is associated with enhanced glutamate transmission
from the PFC and amygdala into the VTA. These lasting changes result from upregulation of short-lived CREB
and sustained elevation and accumulation of FosB, especially in the nucleus accumbens. By reducing the
expression of FosB in the nucleus accumbens, the lasting neurological changes associated with the addictive
state can be mitigated, and cocaine addiction can be successfully treated. To date, the search for a medication
that can effect this change has not been successful. One potential unexplored avenue involves targeting D1-D2
heterodimers, which are largely expressed selectively in the medium spiny neurons in the nucleus accumbens
shell. Mounting evidence indicates that selectively agonizing the D1-D2 heterodimers can block upregulation of
CREB and the resulting overexpression of FosB in the nucleus accumbens. Thus, this approach represents a
novel route for treating cocaine abuse and relapse, and holds high potential for treating patients with CUD and
keeping cocaine free patients abstinent. In order to fulfill this goal, we will first focus on the synthesis of novel
heterobivalent molecules which target the D1-D2 heterodimer. Second, we will evaluate the ligands for affinity,
selectivity, and agonist activity at the D1-D2 heteromer complex. The goal of this project is to develop a selective
D1-D2 heterodimer agonist as a novel potential therapy for cocaine use disorders.

## Key facts

- **NIH application ID:** 10415735
- **Project number:** 7U18DA052509-02
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** ANNA Waclawa SROMEK
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $96,867
- **Award type:** 7
- **Project period:** 2021-06-02 → 2023-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415735

## Citation

> US National Institutes of Health, RePORTER application 10415735, New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers (7U18DA052509-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415735. Licensed CC0.

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