Viloxazine

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder in children characterized by inattention and hyperactivity. In current literature, the pathophysiology of ADHD is understood to involve the imbalance of neurotransmitters, especially dopamine (DA) and norepinephrine (NE). The mechanism of action of viloxazine has not been fully elucidated; however, viloxazine is believed to work by modulating the monoaminergic neurotransmitter systems. Viloxazine is a selective and moderate norepinephrine reuptake inhibitor that binds to the norepinephrine transporter and inhibits the reuptake of norepinephrine. It thereby increases extracellular norepinephrine levels across several brain regions.

Viloxazine potentiates serotonergic effects: it was shown to enhance neuronal sensitivity to serotonin and increase serotonin levels in the brain. In vitro, viloxazine is an antagonist at 5-HT2B receptors and an agonist 5-HT2C receptors. 5-HT2B receptors expressed on GABAergic interneurons are involved in tonic inhibitory control of serotonin neurons that innervate the medial prefrontal context; thus, antagonism of 5-HT2B receptors may result in disinhibition and enhanced serotonin release in the brain region.

There is conflicting evidence in the literature that viloxazine increases dopamine levels in the brain via direct or indirect effects. For example, the norepinephrine transporter is also involved in the reuptake of dopamine in the prefrontal cortex and stimulation of 5-HT2C receptors facilitates DA release and enhances dopaminergic transmission in the brain. As dopamine dysregulation in the prefrontal cortex and amygdala is implicated in ADHD pathophysiology, the impact of viloxazine on dopamine levels may contribute to its mechanism of action. However, there is insufficient evidence to conclude this. Viloxazine has a negligible impact on dopamine in the nucleus accumbens and is not associated with an abuse risk.