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  • Further evidence for action mechanism was provided by assays

    2024-02-07

    Further evidence for action mechanism was provided by assays using [3H]nisoxetine, a selective NET inhibitor used as standard radioligand for competitive binding experiments. The results showed dose-dependent blocking of [3H]nisoxetine binding by both xylazine and dexmedetomidine. Nisoxetine binds to NET on a site shared with the triclyclic antidepressant desipramine. The action site of desipramine on blocking of NE reuptake was recently revealed by a study investigating the structure of a NET homolog in complex with the drug. Desipramine was found to bind to the inner end of the extracellular cavity of the transporter, where it prevented conformational changes and blocked substrate uptake by directly locking the gate of the transporter [25]. Our finding that xylazine and dexmedetomidine directly block NET binding of nisoxetines suggests that these agents may interact with the transporter at a region that overlaps the desipramine binding site. In summary, our study demonstrates that α2 adrenergic agonists including xylazine and dexmedetomidine acutely inhibit NET function in a α2-adrenoreceptor-independent manner. This occurs through competitive inhibition of substrate transport, likely through direct interaction with NET at a region that overlaps the antidepressant binding site.
    Conflict of interest
    Acknowledgement This work was supported by Samsung grant (#C-A9-225-3).
    Introduction Attention Deficit Hyperactivity Disorder (ADHD) is a neuropsyhiatric disorder, and a number of genetic factors play role in its etiopathogenesis (Association, 2013). The NECA and their polymorphisms in dopaminergic and adrenergic pathways have been most extensively studied as candidate genes due to high efficacy rates of psychostimulants; a non-stimulant agent, atomoxetine; and alpha agonists; and because a number of studies have indicated dopamine and noradrenalin as the main neurotransmitters related to attention NECA function (Barnes et al., 2011; Biederman and Spencer, 1999; Swanson et al., 2007). Currently, the association of gene polymorphisms in those pathways with ADHD has been clearly put forward (del Campo et al., 2011). Therefore, in the light of heterogeneous clinical picture, the investigators tend to study the effects of genetic polymorphisms on clinical parameters including clinical presentation, treatment response, and adverse effect frequency taking the heterogeneous clinic, endophenotype concept, and the minor effects of a number of genes instead of a major gene into account (Banaschewski et al., 2010; Kebir and Joober, 2011). From this point of view, metabolic pathways that affect the pharmacokinetics of the drugs used in the treatment and the candidate genes in those pathways have been the topics of the current studies (Froehlich et al., 2010; Kieling et al., 2010). NET is a sodium chloride-paired transporter protein that is responsible for noradrenalin reuptake from the synaptic cleft. It has 12 transmembrane regions, is composed of 617 aminoacids, and coded by NET1 gene (Porzgen et al., 1995). NET1 is a suitable gene for research in the genetics of ADHD since NET, placed mainly in the frontal lobe, is responsible for both noradrenalin and dopamine reuptake and noradrenalin-dopamine balance in synaptic cleft is only maintained by NET in this region, noradrenergic signal transduction results in ADHD-like symptoms in rodents, low noradrenalin levels in orbital and dorsal frontal regions have been associated with poor concentration and increased motor activity, and the only FDA-approved non-stimulant treatment option of ADHD, atomoxetine, is a strong and selective NET inhibitor (Faraone and Mick, 2010; Gizer et al., 2009; Russell, 2011). NET1 gene is located at chromosome 16q12.2 (Gelernter et al., 1993). NET1 gene, also known as Solutecarrierfamily 6, member 2 (SLC6A2), is composed of 14 exons and 13 introns (Pacholczyk et al., 1991). Alpha-2 receptors are located in the presynaptic region, and carry inhibitory properties. They have 3 subtypes: A, B and C (Aoki et al., 1994). Among them, ADRA2A is the most widely distributed subtype in the brain including prefrontal cortex, amygdala, hippocampus, and locus ceruleus (Aoki et al., 1994). ADRA2A has been noted as a candidate gene of ADHD since noradrenergic system play role in executive functions such as wakefulness and regulation of attention, ADRA2A is mainly responsible for a number of executive functions particularly in medial prefrontal cortex, animal studies indicated that stimulation of noradrenergic projections resulted in improvement in cortical functions, and presynaptic alpha-2 receptor agonists, clonidine and guanfacine, have been used in treatment of ADHD for a long time (Arnsten et al., 1996; Bidwell et al., 2010; Biederman and Spencer, 1999). ADRA2A is situated at chromosome 10q23-q25 (Yangfeng et al., 1987).