Exendin-4 induced retching-like behavior mediated by postsynaptic effect via AMPA receptors in the area postrema of...

Although glucagon-like peptide-1 (GLP-1) analogs have been clinically approved for type 2 diabetes mellitus (T2DM) and obesity treatment for an extended period, their associated adverse effects of nausea and vomiting remain unsolved. To elucidate the neural mechanisms underlying GLP-1-induced emesis, we investigated how GLP-1 signaling in the area postrema (AP) modulates retching-like behavior in mice. Our experiments demonstrated that intraperitoneal administration of the GLP-1 receptor agonist Exendin-4 (Exn4) induced dose-dependent retching-like behavior, which was replicated by direct Exn4 administration into the AP. Notably, while vagal afferent denervation failed to attenuate Exn4-induced retching-like behavior, genetic ablation of GLP-1 receptor (GLP-1R) expression in the AP completely abolished this response, establishing AP GLP-1R as the critical mediator of GLP-1-associated emesis. Further mechanistic studies revealed that Exn4 enhances AP GLP-1R neuronal activity through a postsynaptic pathway dependent on AMPA receptor signaling. These findings provide a neural circuit basis for GLP-1-induced emesis and identify a potential therapeutic target for mitigating this clinically significant side effect.NEW & NOTEWORTHY Here, we used a mouse-based paradigm to identify that the retching-like behavioral effects are caused by direct central GLP-1R neurons activation in the caudal brainstem, independent of the vagal afferent pathway. Importantly, the activation of AP^GLP-1R is mediated by postsynaptic AMPA receptors, which strengthen excitatory currents. Thus, we revealed the target and neural basis of GLP-1 analog-induced vomiting effect, which highlights a potential intervening site for clinical treatment.