Activation of GLP-1 receptors suppresses pathological defensive aggression via DMPAG in mice

Defensive aggression is an evolutionarily conserved instinct, and its dysregulation represents a common behavioral manifestation in multiple psychiatric disorders. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic diseases, their role in aggressive behavior remains unclear. Here, we employed behavioral assays, chemogenetics, immunofluorescence, pharmacological manipulations, and metabolomics to investigate the regulatory effects of GLP-1RA on defensive aggression in mice. Acute intracerebroventricular administration of GLP-1RA significantly suppressed defensive aggression without affecting locomotor activity or time spent in the center of the open field. c-Fos immunofluorescence indicated that this effect was associated with reduced neuronal activity in the dorsomedial periaqueductal gray (DMPAG). Chemogenetic activation of DMPAG neurons reversed the suppressive effect of GLP-1RA on defensive aggression, supporting a key regulatory role of this region. In a social isolation (SI) induced pathological aggression model, GLP-1RA alleviated excessive defensive aggression and modulated the metabolic state of the DMPAG. Notably, GLP-1RA restored levels of L-carnosine, a dipeptide with neuroprotective and anti-excitotoxic properties whose levels were reduced in SI mice. Carnosine infusion into the DMPAG suppressed defensive aggression in SI mice, whereas administration of the carnosine degrading enzyme CNDP2 attenuated the suppressive effect of GLP-1RA, supporting carnosine signaling as a functionally relevant downstream component. These findings identify a carnosine-associated pathway by which GLP-1RA regulates defensive aggression and highlight its therapeutic potential beyond metabolic regulation.