Phenytoin inhibits isolation-induced aggression specifically in rats with low serotonin

Phenytoin is a widely used anticonvulsant drug that also reduces aggressive behavior. Aggression in humans and animals is often associated with low serotonin levels. This study examined the anti-aggressive properties of phenytoin in rodent isolation-induced aggression using a resident-intruder test to quantify aggression. Chronic treatment with p-chlorophenyl-alanine (PCPA), a competitive inhibitor of serotonin synthesis, significantly enhanced resident attack behavior compared to saline-treated control rats. Phenytoin dose-dependently reduced aggressive behavior specifically in PCPA-treated rats, but had no anti-aggressive properties in saline-treated rats. These data suggest that aggressive behavior in this model may be related to neuronal hyperexcitability that is sensitive to the anticonvulsant effects of phenytoin. Further, these data suggest isolation-induced aggression in PCPA-treated rats may be a useful model to investigate aggression associated with low serotonin in the brain.