Central Glp-1 Antagonists-Induced Hyperphagia

Polyphagia, orhyperphagia, is an abnormally strong, incessant sensation of hunger or desire to eat often leading to overeating. In contrast to an increase in appetite following exercise, polyphagia does not subside after eating and often leads to rapid intake of excessive quantities of food.

Preclinical evidence consistently demonstrated thatGLP-1RAs, including exendin-4, liraglutide, and semaglutide, reduced substance intake, relapse-like behaviors, and cue-induceddrug seeking across multiple drug classes.

GLP-1receptor agonist (GLP-1RA) therapies were developed to mimic the peripheral effects ofGLP-1, but it is now well established that their efficacy in the treatment of obesity depends on reducing energy intake through their action in thecentralnervous system (CNS).

We found thatcentraldelivery of theGLP-1R agonist Exendin-4 suppressed theinductionof phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core.

Stimulation ofGLP-1receptorinducessuppression of appetite, inhibition of gastric emptying, and an increase in insulin secretion [19].10. Ho J, Cox JM, Wagner EJ, Cannabinoid-inducedhyperphagia: correlation with inhibition of proopiomelanocortin neurons?

ICV administration ofGLP-1receptors in the CNS reduces food intake, andGLP-1RAsinducehyperphagia. Circulating levels ofGLP-1, including responses to meals, are decreased in obese individuals.

CentralinjectionGLP-1failed toinducetachycardia in vagotomised rats, suggesting that the vagus nerve (a principle effector of parasympathetic tone) is required for Ex-4 toinducetachycardia (Barragán et al., 1999).

Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects ofGLP-1R agonist monotherapy on nicotine seeking and withdrawal-inducedhyperphagiaare unknown.