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

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. 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 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.