Tirzepatide reduces alcohol drinking, modulates reward processing, and alters lateral septum proteome in preclinical models of AUD

This study explored the therapeutic potential of tirzepatide, a dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist, in preclinical models of AUD, while elucidating the neurobiological mechanisms mediating its effects. Our methodological approach involved reward-related behaviors, alcohol consumption paradigms, and molecular techniques including neurochemical, neurophysiological, and proteome analysis in rodents. Tirzepatide administration attenuated alcohol-induced locomotor stimulation, conditioned place preference, and accumbal dopamine release. Global proteomic analysis revealed altered histone and chromatin regulatory proteins in the lateral septum of tirzepatide-treated alcohol-consuming rats.