New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers

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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.