GLP-1 receptor agonist semaglutide reduces appetite while increasing dopamine reward signaling

Semaglutide, a glucagon-like peptide-1 receptor agonist, is an effective drug reducing body weight and decreasing motivation for palatable food. The mechanisms underlying its effects on food reward remain unclear. We aimed to determine the impact of semaglutide on food reward collection and dopamine-neuron activity in the ventral tegmental area (VTA) upon exposure to a cue-induced sucrose delivery task. Pitx3-cre mice were injected with cre-dependent GCaMP6s virus into the VTA, to measure the activity of dopaminergic neurons in the VTA using in vivo fiber photometry. Mice were trained on a Pavlovian sucrose conditioning paradigm in which a 5-s cue signaled a 20% sucrose reward. Upon stable performance, semaglutide or vehicle was intraperitoneally injected during the task. 1 mg/kg semaglutide reduced the number of collected rewards and licks during the task. Semaglutide increased VTA dopamine neuron activity during sucrose collection but not during the cue. Lower doses of semaglutide (0.1 and 0.3 mg/kg) reduced chow intake but not sucrose intake nor VTA dopamine activity in the task. Semaglutide reduces appetite but increases VTA dopamine signaling during reward collection. Semaglutide does not influence dopamine signaling during the presentation of food cues.