**Background**
Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by persistent patterns of inattention, hyperactivity, and impulsivity. These symptoms are closely linked to dysregulation of key neurotransmitters in the prefrontal cortex and other brain regions, particularly norepinephrine (NE), dopamine (DA), and serotonin (5-HT). Modulating the levels of these monoamines in the synaptic cleft is a primary therapeutic strategy for managing ADHD symptoms and improving cognitive function. Consequently, the development of selective inhibitors and receptor modulators that can precisely tune these neurotransmitter systems is of significant research importance. In this context, we will introduce a selective norepinephrine transporter inhibitor and 5-HT receptor modulator – Viloxazine.
**Definition**
Viloxazine is a non-brain-penetrant, selective norepinephrine transporter (NET) inhibitor with an IC50 value of 0.26 μM, which also acts as a modulator of 5-HT receptors.
**In Vitro and In Vivo Studies**
According to the Viloxazine description, this compound functions by competitively inhibiting NET to increase NE and DA levels in the synaptic cleft. It further enhances 5-HT neurotransmission by acting as an antagonist at 5-HT2B receptors (Ki = 4.2 μM) and an agonist at 5-HT2C receptors (EC50 = 32 μM). Regarding Viloxazine in vitro activity, a kinase binding assay using 10 μM of the compound demonstrated significant inhibition of 7 out of 132 targets, including NET, 5-HT2B, 5-HT2C, 5-HT1B, 5-HT7, ADR α1A, and ADR α1B receptors, showing the highest selectivity for NET with an inhibition rate exceeding 50%.
The Viloxazine biological activity has been further validated through extensive animal studies. In vivo studies using male Sprague-Dawley rats (300-400 g, 7-8 weeks) showed that a single intraperitoneal injection of 50 mg/kg significantly increased extracellular NE, DA, and 5-HT levels in the prefrontal cortex (PFC), nucleus accumbens (Acb), and amygdala (Amg), with peak responses occurring at 60 minutes post-injection (NE: 649%, DA: 670%, and 5-HT: 506% of baseline). Additionally, doses ranging from 1 to 30 mg/kg (i.p.) dose-dependently increased NE and 5-HT levels in the PFC, while significantly decreasing the NE metabolite DHPG at 10 and 30 mg/kg, without significantly affecting DA levels. The median lethal dose (LD50) was reported as 500-1000 mg/kg (p.o., mouse), 2000 mg/kg (p.o., rat), and 60 mg/kg (i.v., mouse). In conclusion, Viloxazine is a potent NET inhibitor and 5-HT receptor modulator that effectively increases monoamine levels in key brain regions, making it a valuable tool for ADHD research.
Keywords
Viloxazine, 35604-67-2, Viloxazin, Emovit, 5-HT Receptor, Serotonin Receptor, 5-hydroxytryptamine Receptor, Serotonergic, noradrenergic, 5-HT, depression, Inhibitor, inhibitor, inhibit
References
[1] Yu C, et al. New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties. J Exp Pharmacol. 2020 Aug 25;12:285-300.
[2] Garcia-Olivares J, et al. 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. J Exp Pharmacol. 2024 Jan 16;16:13-24.
[3] Findling RL, et al. Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status. CNS Drugs. 2021 Jun;35(6):643-653.