Gut-brain peptides and drugs of abuse: highlighting the role of GLP-1 and amylin

Abstract

Alcohol use disorder (AUD) and cocaine use disorder (CUD) are complex conditions with diverse neurobiological foundations. Current treatments for AUD and CUD are suboptimal; gaining a deeper understanding of the underlying mechanisms could aid in identifying more effective treatment options. While various factors play a role in AUD and CUD progression, the rewarding effect of the drug of abuse, primarily driven by increased dopamine levels in the nucleus accumbens (NAc), remains a central mechanism. Previous studies have demonstrated that targeting gut-brain peptides, such as glucagon-like peptide-1 receptor (GLP-1R) and the amylin receptor (AMYR), decreases the intake of alcohol and cocaine through modulation of the reward circuitry. However, there are still unexplored opportunities to enhance the efficacy of potential treatment strategies involving GLP-1R and AMYR for AUD and CUD. This thesis, therefore, explores the potential of semaglutide, a highly potent GLP-1R agonist, and the combination of GLP-1R and AMYR agonists to improve outcomes. Additionally, this thesis investigates a brain region involved in the reward context, the paraventricular nucleus of the thalamus (PVT), and the unexplored role of AMYR within this area. First, low doses of semaglutide demonstrated a reduction of alcohol- and cocaine-related responses in rodents, likely through its influence on the reward circuitry. Second, a combination of GLP-1R and AMYR agonists revealed a synergistic-like reduction of alcohol intake in male rats. Third, infusion of sCT into the middle part of PVT reduced alcohol intake in males but not in females, potentially due to sex-specific differences in projections to the NAc. Together, the studies presented in this thesis provide novel insight into enhancing the efficacy of GLP-1R and AMYR agonists in modulating alcohol- and cocaine-related responses while also offering new knowledge about the underlying mechanisms involved. These findings provide the advantage of maintaining effective drug intake reduction while enabling the use of lower doses, thereby minimizing potential side effects. Importantly, several studies in this thesis underline differences in responses between males and females, stressing the importance of conducting further research that includes both sexes to optimize treatment strategies for both men and women. In conclusion, this thesis highlights the significant potential of GLP-1R and AMYR agonists as therapeutic options for AUD and CUD.