Central GLP-1 receptors: Novel molecular targets for cocaine use disorder

Given that the search for effective pharmacotherapies for cocaine use disorder has, thus far, been fruitless, there remains a critical need for conceptually innovative approaches toward identifying new medications to treat this disease. A better understanding of the neurocircuits and neurobiological mechanisms underlying cocaine taking and seeking may identify molecular substrates that could serve as targets for novel pharmacotherapies to treat cocaine use disorder. Recent preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) receptor agonists could be re-purposed to treat cocaine craving-induced relapse. This review endeavors to comprehensively summarize the current literature investigating the efficacy of GLP-1 receptor agonists in reducing the rewarding and reinforcing effects of cocaine in animal models of cocaine use disorder. The role of central endogenous GLP1 circuits in voluntary cocaine taking and seeking is also discussed. Behavioral, neurochemical, electrophysiological and molecular biology studies indicate that central GLP-1 receptor activation functionally modulates the mesolimbic reward system and decreases addiction-like phenotypes in rodents. Overall, an emerging preclinical literature provides compelling evidence to advance GLP-1 receptor agonists into clinical trials testing the efficacy of these medications in preventing cocaine craving-induced relapse.