title: Altered gene expression in the prefrontal cortex of young rats induced by the ADHD drug atomoxetine.
abstract: Atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, is a non-stimulant approved for the treatment of attention deficit/hyperactivity disorder (ADHD). Little is known about the molecular basis for its therapeutic effect. The objective of this animal study was to determine alterations in gene expression patterns in the prefrontal cortex after long-term administration of atomoxetine. Rats were treated for 21 days during childhood and early adolescent stages of development with a once-daily oral application of 0.05 g/kg atomoxetine, which resulted in plasma levels similar to those described in children. A whole genome RNA-microarray of rat prefrontal cortical gene expression after administration of atomoxetine versus sterile water revealed an mRNA increase in 114 genes (≥2-fold) while 11 genes were down-regulated (≤0.5-fold). By applying quantitative real-time PCR (qRT-PCR) and Western Blot we confirmed a significant increase in the expression of GABA A receptor subunits as well as ubiquinol-cytochrome c reductase complex core protein 2 (Uqcrc2). SNAP-25 (synaptosomal-associated protein of 25 kDa), which is an ADHD candidate gene and an important vesicle protein involved in axonal growth, synaptic plasticity and regulation of neurotransmitter release was also significantly upregulated on RNA- and protein level after atomoxetine treatment. In summary, we could show that long-term treatment with the ADHD drug atomoxetine induces the regulation of several genes in the prefrontal cortex of young rats. Especially the increased expression of SNAP-25 and GABA-A receptor subunits may indicate additional active therapeutic mechanisms for atomoxetine.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University Hospital Frankfurt, Deutschordenstrasse 50, 60528 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lempp
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Toennes
authors.forename: Cora
authors.initials: C
authors.lastname: Wunder
authors.forename: Otto Quintus
authors.initials: OQ
authors.lastname: Russe
authors.forename: Christine V
authors.initials: CV
authors.lastname: Möser
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kynast
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freitag
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D011437:Propylamines; D011963:Receptors, GABA-A; D050825:Synaptosomal-Associated Protein 25; D000069445:Atomoxetine Hydrochloride; D014450:Electron Transport Complex III