Viloxazine Increases Extracellular Concentrations of Norepinephrine, Dopamine, and Serotonin in the Rat Prefrontal Cortex at Doses Relevant for the Treatment of Attention-Deficit/Hyperactivity Disorder

Abstract

Background

Viloxazine ER (viloxazine extended-release capsules; Qelbree^®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations.

Methods

Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies).

Results

Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT.

Conclusion

At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.

Plain Language Summary

Viloxazine ER (Qelbree^®) is a non-stimulant, FDA-approved treatment for ADHD in children and adults. Viloxazine and other ADHD medications are thought to work by increasing two signaling molecules, called norepinephrine and dopamine, in a brain area called the prefrontal cortex. The prefrontal cortex is important in ADHD as it helps control impulsive behavior, attention, hyperactivity, and learning. A third signaling molecule called serotonin may also be important for ADHD. Previous experiments in rats have shown that viloxazine increases norepinephrine, dopamine, and serotonin in the prefrontal cortex. To better understand how viloxazine increases serotonin and if the increase occurs at the same doses used to treat ADHD, we did another microdialysis study in rats. Our study showed that viloxazine increases norepinephrine, dopamine, and serotonin in the prefrontal cortex at doses used to treat ADHD in humans. We showed that viloxazine increases norepinephrine and dopamine levels in the neuron where these signaling molecules work by blocking the way that they are recycled back into the nerve space. However, viloxazine does not block the serotonin recycling mechanism, meaning viloxazine works differently than selective serotonin reuptake inhibitor (SSRI) medications (often used in depression). Additional studies are needed to determine exactly how viloxazine increases serotonin in the brain and whether this increase plays a role in treating ADHD. These additional studies will also help us understand how viloxazine acts differently than other ADHD medications.

Graphical Abstract

Keywords:

• viloxazine
• microdialysis
• prefrontal cortex
• serotonin
• NET
• ADHD

Acknowledgments

Kobby Asubonteng for assistance with statistical analysis.

Disclosure

JG-O, BY, JE, JK, CY are employees of Supernus Pharmaceuticals, Inc. FB is an employee of Bymaster Neuroscience Consulting and a consultant for Supernus Pharmaceuticals, Inc. JR is an employee of Supernus Pharmaceuticals, Inc. and reports stock options and grants from Supernus Pharmaceuticals, Inc.

Additional information

Funding

This study was fully funded by Supernus Pharmaceuticals, Inc.