Chronic semaglutide treatment enhances the incentive motivational value of a small food reward and associated cue in male and female rats

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, are increasingly utilized in clinical practice due to their efficacy in promoting sustained weight loss following chronic administration. While acute treatment with GLP-1 receptor agonists has been shown to suppress food intake and reward-seeking behaviors in rodent models, the impact of prolonged exposure on preclinical measures of motivated behavior remains insufficiently characterized. This study aimed to systematically evaluate the effects of chronic administration of semaglutide on both the acquisition and expression phases of Pavlovian conditioned approach (PavCA), a behavioral paradigm used to assess the attribution of incentive salience to a food-paired cue. The influence of chronic semaglutide on the conditioned reinforcing properties of the food-associated cue, performance on a progressive ratio (PR) schedule for food reward, and ad libitum consumption of the food reward were also assessed. Chronic semaglutide administration did not significantly alter either the acquisition or the expression of PavCA behavior. However, relative to vehicle-treated controls, semaglutide markedly enhanced responding for the food-associated cue during a conditioned reinforcement test and increased PR responding for the food reward. In contrast, semaglutide reduced both free consumption of the food reward and homecage chow intake. These findings demonstrate that chronic semaglutide administration potentiates the incentive value of food-paired cues and increases motivation for food reward under restricted access conditions, yet attenuates overall food consumption when food is freely available. This dissociation highlights the nuanced effects of semaglutide on motivated behavior and suggests an amplification of the reinforcing properties of discrete, limited food rewards and associated cues.