Antiepileptic drugs have been shown to be associated with inducing or exacerbating adverse psychotropic reaction, including aggressive behavior. Perampanel, the first pharmacological compound approved by the FDA in 2012, is an effective antiepileptic drug for intractable epilepsy but induces severe aggression. So far, the underlying molecular mechanisms of aggression induced by perampanel remain incompletely understood. In the present study, a model of aggressive behavior based on the clinical use of perampanel was established and resident-intruder test and open field test were performed. Changes in hippocampal protein profiles were detected by tandem mass tag (TMT) proteomics. The behavioral results indicated that long-term use of perampanel increased the aggressive behavior of C57BL/6J mice. Proteomic analysis revealed that 93 proteins were significantly altered in the hippocampus of the perampanel-treated group (corrected