Plumbagin reduces anger-like phenotype in rats by suppressing nitric oxide signaling and enhancing serotonergic transmission in the central nucleus of the amygdala.

Abstract

Intermittent explosive disorder (IED) is characterized by impulsive outbursts of anger and violent behavior, involving dysregulation of limbic circuits underlying emotional and behavioral control. Neuronal nitric oxide synthase (nNOS)-derived nitric oxide may modulate serotonergic neurotransmission involved in anger regulation. Current treatments for IED are limited, and the therapeutic potential of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a compound with anti-inflammatory and neuroprotective properties, has not been explored for its effects on anger. This study aimed to test the effect of plumbagin on anger-like behavior, focusing on its impact on the nitric oxide and serotonin systems in the amygdala. Herein, we assessed the effects of plumbagin on nNOS expression and nitric oxide levels in the central nucleus of the amygdala (CeA) of rats fasted for 24-hr and subjected to roller rotation and biting activity chambers. The effects of plumbagin, the nNOS inhibitor 7-nitroindazole (7-NI), and their combination were tested through intraperitoneal injections. Intra-CeA administration of 7-NI was also evaluated. nNOS expression, nitric oxide, and serotonin levels in the CeA were measured via immunohistochemistry, RT-qPCR, colorimetric assay, and HPLC, respectively. Rats showed increased roller rotation and biting activity, elevated nNOS expression and nitric oxide concentrations, and decreased serotonin levels in the CeA. The nNOS expression in the basolateral amygdala was unchanged. However, systemic administration of plumbagin, 7-NI, and their combination reversed these changes. Additionally, administration of 7-NI directly in the CeA attenuated the anger-like behaviors. Plumbagin might reduce nitric oxide signaling in the CeA, which was accompanied by increased serotonin levels and reduced anger-like behaviour.