Repeated risperidone administration during puberty prevents the generation of the aggressive phenotype in a developmentally immature animal model of escalated aggression

Risperidone has been shown to be clinically effective for the treatment of aggressive behavior in children, yet until recently no information was available regarding whether risperidone exhibits aggression-specific suppression in preclinical studies employing validated developmentally immature animal models of escalated aggression. Recently, using a pharmacologic animal model of escalated offensive aggression, we reported that acute risperidone treatment selectively and dose-dependently reduces the expression of the adult aggressive phenotype, with a significant reduction in aggressive responses observed at 0.1 mg/kg, i.e., a dose within the range administered to children and adolescents in the clinical setting. This study examined whether repeated exposure to risperidone during puberty would prevent the generation of the highly escalated aggressive phenotype in this animal model. To test this hypothesis, the aggression-eliciting stimulus (i.e., cocaine hydrochloride, 0.5 mg/kg/day × 28 days) was co-administered with an aggression-suppressing dose of risperidone (i.e., 0.1 mg/kg/day) during different time frames of puberty and for varied lengths of time (i.e., 1–4 weeks), and then animals were scored for targeted measures of offensive aggression during late puberty. Risperidone administration prevented the generation of the adult aggressive phenotype, with a complete blockade of matured offensive responses (i.e., lateral attacks and flank/rump bites) seen only after prolonged periods of exposure to risperidone (i.e., 3–4 weeks). The selective prevention of these aggressive responses, while leaving other measures of aggression intact (e.g., upright offensive postures), suggest that risperidone is acting in a highly discriminatory anti-aggressive fashion, targeting neurobehavioral elements important for the mature aggressive response pattern.