New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties

Overview

Journal J Exp Pharmacol

Publisher Dove Medical Press

Date 2020 Sep 18

PMID 32943948

Citations 41

Authors

Chungping Yu

Jennie Garcia-Olivares

Shawn Candler

Stefan Schwabe

Vladimir Maletic

Affiliations

Soon will be listed here.

Abstract

Background: Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy.

Methods: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats.

Results: We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT and agonistic activity at 5-HT receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems.

Conclusion: Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).

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References

Whitestone S, De Deurwaerdere P, Baassiri L, Manem J, Anouar Y, Di Giovanni G . Effect of the 5-HT Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study. Int J Mol Sci. 2019; 20(12). PMC: 6627111. DOI: 10.3390/ijms20122925. View

Bymaster F, Katner J, Nelson D, Hemrick-Luecke S, Threlkeld P, Heiligenstein J . Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002; 27(5):699-711. DOI: 10.1016/S0893-133X(02)00346-9. View

Conio B, Martino M, Magioncalda P, Escelsior A, Inglese M, Amore M . Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders. Mol Psychiatry. 2019; 25(1):82-93. DOI: 10.1038/s41380-019-0406-4. View

Wong E, Sonders M, Amara S, Tinholt P, Piercey M, Hoffmann W . Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry. 2000; 47(9):818-29. DOI: 10.1016/s0006-3223(99)00291-7. View

Oades R, Myint A, Dauvermann M, Schimmelmann B, Schwarz M . Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention. Behav Brain Funct. 2010; 6:32. PMC: 2900218. DOI: 10.1186/1744-9081-6-32. View

Cathala A, Devroye C, Drutel G, Revest J, Artigas F, Spampinato U . Serotonin receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons. Exp Neurol. 2018; 311:57-66. DOI: 10.1016/j.expneurol.2018.09.015. View

Oades R . Dopamine may be 'hyper' with respect to noradrenaline metabolism, but 'hypo' with respect to serotonin metabolism in children with attention-deficit hyperactivity disorder. Behav Brain Res. 2002; 130(1-2):97-102. DOI: 10.1016/s0166-4328(01)00440-5. View

Jenck F, Moreau J, Berendsen H, Boes M, Broekkamp C, Martin J . Antiaversive effects of 5HT2C receptor agonists and fluoxetine in a model of panic-like anxiety in rats. Eur Neuropsychopharmacol. 1998; 8(3):161-8. DOI: 10.1016/s0924-977x(97)00055-2. View

Navailles S, Moison D, Cunningham K, Spampinato U . Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine. Neuropsychopharmacology. 2007; 33(2):237-46. DOI: 10.1038/sj.npp.1301414. View

10.

Miyazaki K, Miyazaki K, Doya K . The role of serotonin in the regulation of patience and impulsivity. Mol Neurobiol. 2012; 45(2):213-24. PMC: 3311865. DOI: 10.1007/s12035-012-8232-6. View

11.

Delguidice T, Lemay F, Lemasson M, Levasseur-Moreau J, Manta S, Etievant A . Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation. Neuropsychopharmacology. 2013; 39(5):1125-34. PMC: 3957106. DOI: 10.1038/npp.2013.313. View

12.

Miyazaki K, Miyazaki K, Doya K . Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards. J Neurosci. 2012; 32(31):10451-7. PMC: 6621383. DOI: 10.1523/JNEUROSCI.0915-12.2012. View

13.

Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke H, Kettenmann H . Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun. 2011; 26(3):419-28. DOI: 10.1016/j.bbi.2011.12.002. View

14.

Arnsten A . The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex. J Pediatr. 2010; 154(5):I-S43. PMC: 2894421. DOI: 10.1016/j.jpeds.2009.01.018. View

15.

Wong D, Threlkeld P, Best K, Bymaster F . A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain. J Pharmacol Exp Ther. 1982; 222(1):61-5. View

16.

Devroye C, Cathala A, Di Marco B, Caraci F, Drago F, Piazza P . Central serotonin(2B) receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow. Neuropharmacology. 2015; 97:329-37. DOI: 10.1016/j.neuropharm.2015.06.012. View

17.

Felger J, Lotrich F . Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013; 246:199-229. PMC: 3741070. DOI: 10.1016/j.neuroscience.2013.04.060. View

18.

Whitney M, Shemery A, Yaw A, Donovan L, Glass J, Deneris E . Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci. 2016; 36(38):9828-42. PMC: 5030349. DOI: 10.1523/JNEUROSCI.1469-16.2016. View

19.

Arnsten A . Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry. 2006; 67 Suppl 8:7-12. View

20.

Lippman W, Pugsley T . Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities. Can J Physiol Pharmacol. 1976; 54(4):494-509. DOI: 10.1139/y76-069. View