Endocrine Abstracts

Addiction is a major health and socioeconomic burden for individuals and society. The need for new treatments is substantial, and peptides of the gut-brain axis, including glucagon-like peptide 1 receptor (GLP-1R) agonists, have been suggested as potential options. Early preclinical studies revealed that GLP-1R agonists attenuate both alcohol- and drug-associated behaviors. The newest generation of GLP-1R agonists, such as semaglutide and tirzepatide, have been tested in relation to addiction. The aim of our preclinical research aims to evaluate the role of the gut-brain axis in addiction. Acute or repeated administration of semaglutide substantially reduced alcohol intake and blocked relapse-drinking in male and female rats. Furthermore, semaglutide acutely suppressed the alcohol-induced locomotor stimulation and reduced the dopamine release in the nucleus accumbnes (NAc), a brain region central for addiction and were semaglutide was detected in alcohol-drinking rodents. On a similar note, semaglutide prevented the rewarding properties of cocaine and reduced the intake, motivation, and relapse to cocaine taking in male rats. Extensive experience then tested tirzepatide, an agonist with an even more profound affinity to the GLP-1R, and affinity to the GIP receptors. These studies show that tirzepatide, once or repeatedly, reduced the intake of alcohol across sexes in various alcohol drinking models. It blocked the rewarding properties of alcohol, which was suppressed, and electrophysiological studies pinpointed the lateral septum (LS) as an important region regulating the above-mentioned areas. In support, proteomics revealed a disruption of histones in LS by alcohol, and this effect was restored by tirzepatide. It should be further noted that GLP-1R in LS was also central in mediating the alcohol-mediated behaviors. In summary, these preclinical data suggest a central role for the gut-brain axis in regulating addiction in rodents deserving further clinical studies.