Bidirectional effects of Topiramate on anterior cingulate cortex region related aggressive behavior

Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations as well as in animal models of aggression. However, increases in aggression were also observed under lower doses of Topiramate. Subsequently, Topiramate produced an inverted U-shaped dose response curve, with increases in aggression at low doses, whereas higher doses engendered anti-aggressive effects. In our previous study, we demonstrated that Topiramate modulates brain activity in the prefrontal areas involved in the modulation of the subcortical circuit mediating aggression, and we found indirect evidence that the anterior cingulate cortex (ACC) could be a key site where Topiramate may exert its dose-response effects on aggression. In this study, we performed site-directed injections of Topiramate (0.1 and 0.3 mM) into the ACC on offensive behaviors in isolation-inducedaggression paradigm. By using the resident-intruder test, we demonstrated that Topiramate microinfusion into the ACC at low doses produced increases in aggression, as evidenced by shorter attack latencies (p < 0.01) and increased attack duration (p < 0.01), without affecting the social behavior. In contrast, higher doses engendered anti-aggressive effects, by increasing the attack latencies (p < 0.001), decreasing attack number (p < 0.001) and decreasing attack duration (p < 0.001), as well as an increase in the social behavior. Our findings supported that Topiramate at higher concentrations appeared more efficient to decrease aggression in treated mice. Therefore, we suggest that the ACC is a key brain region in which Topiramate may exert its dose-response effects on aggressive and antisocial behaviors observed in populations with psychotic disorders.