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

> **NIH NIH U18** · MCLEAN HOSPITAL · 2020 · $119,767

## 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 2018, reaching almost 14,000. Currently, there are no FDA
approved medications available for treating cocaine addiction. 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 cocaine abusers and keeping cocaine-
free abusers 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 addiction.

## Key facts

- **NIH application ID:** 10107211
- **Project number:** 1U18DA052509-01
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** ANNA Waclawa SROMEK
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $119,767
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-05-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107211

## Citation

> US National Institutes of Health, RePORTER application 10107211, New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers (1U18DA052509-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107211. Licensed CC0.

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