Dopamine D2 receptor modulation of insulin receptor signaling in the central amygdala: implications for compulsive-like eating behavior

Compulsive eating behavior, characterized by the excessive intake of palatable high-sugar and high-fat foods despite negative consequences, may be associated with dysfunctional dopamine system, specifically involving the dopamine D2 receptors (D2Rs). Here, we demonstrate that D2Rs regulate insulin receptor (InsR) signaling in the central amygdala, and this interaction plays a critical role in the persistent, compulsive-like palatable food-seeking behavior. The specific ablation of D2Rs in the CeA markedly enhances compulsive-like eating despite adverse consequences. We observed significant colocalization of D2Rs and InsRs in the CeA, where the loss of D2Rs resulted in decreased InsR expression and impaired insulin signaling. Pharmacological activation of D2Rs facilitated InsR phosphorylation and subsequent insulin signaling, highlighting a critical modulatory role of D2Rs on InsR function. These findings underscore the importance of D2R and InsR interactions in the CeA in fine-tuning brain insulin sensitivity and managing normal or maladaptive eating. This study offers novel insights into the interplay between dopamine and insulin signaling, with implications for understanding neurological disorders linked to metabolic and reward dysregulation.