Abstract
Cocaine use disorder (CUD) is a major public health challenge with a high relapse rate and lack of effective pharmacotherapies; therefore, there is a substantial need to identify novel medications to treat this epidemic. Since the advent of glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) agonists (GLP-1RAs), their potential has been extensively explored and expanded. In this review, we first summarized the biological effects of GLP-1, GLP-1Rs, and GLP-1RAs. Subsequently, the recent literature examining the behavioral effects and the possible pharmacological mechanisms of GLP-1RAs on CUD was reviewed. Increasing preclinical evidence suggests that GLP-1RAs are promising in regulating dopamine release, dopamine transporter (DAT) surface expression and function, mesolimbic reward system and GABAergic neurons, and maladaptive behaviors in animal models of self-administration and conditioned place preference. In addition, the emerging role of GLP-1RAs in inhibiting inflammatory cytokines was reported. These findings indicate that GLP-1RAs perform essential functions in the modulation of cocaine-seeking and cocaine-taking behaviors likely through multifaceted mechanisms. Although the current preclinical evidence provides convincing evidence to support GLP-1RA as a promising pharmacotherapy for CUD, other questions concerning clinical availability, impact and specific mechanisms remain to be addressed in further studies.
Highlights
Cocaine is an extraordinarily addictive drug extracted from the Erythroxylon coca plant which was originally used to relieve local pain (Biondich and Joslin, 2016)
N-acetylcysteine reduced cocaine intake and locomotor sensitization as well as reinstatement in animal models but had no effect on cocaine intake in humans (Madayag et al, 2007). Consistent with this data, the recent human study demonstrated that exenatide diminished levels of glucagon-like peptide-1 (GLP-1) and insulin but failed to show inhibitory effects on cocaine-associated behaviors (Angarita et al, 2021), indicating that more clinical studies are needed to investigate the effects of GLP-1 on patients with Cocaine use disorder (CUD)
In addition to regulating the release of neurotransmitters including dopamine, GABA, and glutamate, GLP-1RAs may have an important role in cocaine reward by reducing inflammation
Summary
Cocaine is an extraordinarily addictive drug extracted from the Erythroxylon coca plant which was originally used to relieve local pain (Biondich and Joslin, 2016). Preclinical literature shows that GLP-1RAs have important impacts on the regulation of dopamine release as well as on the mesolimbic reward system and the amelioration of cocaine-mediated behavior in animal models of CUD (Hernandez and Schmidt, 2019).
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