title: Atomoxetine increases histamine release and improves learning deficits in an animal model of attention-deficit hyperactivity disorder: the spontaneously hypertensive rat.
abstract: Substantial development in the pharmacological treatment for attention-deficit hyperactivity disorder (ADHD) has been made recently including approval of new non-stimulant agents targeting noradrenergic, histaminergic and dopaminergic systems. Among such, atomoxetine has been widely used, although its mechanism of action is poorly understood. It is known that central nervous system histamine is closely associated with cognition and it was recently shown that both atomoxetine and methylphenidate enhance cortical histamine release in rats. To that end, the aim of our study was to investigate the effect of atomoxetine (2 mg/kg, intraperitoneally) on histamine release using the microdialysis technique in the spontaneously hypertensive rat (SHR), a suitable genetic model for ADHD. Our data confirmed that atomoxetine increases extracellular levels of histamine in the prefrontal cortex, a brain region that is implicated in the pathophysiology of ADHD. Given the tie between histamine neurotransmission and treatment of cognitive dysfunction, we also assessed the effects of atomoxetine on learning and memory as measured by the Morris water maze in SHR. The results indicated that atomoxetine significantly ameliorated performance in the Morris water maze, consistent with its histamine-enhancing profile. In conclusion, the current study provides further support for the notion that the therapeutic effect of atomoxetine could involve activation of histamine neurotransmission within the prefrontal cortex.
authors.affiliation: Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Ge-Fei
authors.initials: GF
authors.lastname: Lei
authors.forename: Gui-Ju
authors.initials: GJ
authors.lastname: Wang
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Wang
authors.forename: Ruo-Peng
authors.initials: RP
authors.lastname: Sun
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D006632:Histamine / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011437:Propylamines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D014867:Water
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D014867:Water; D000069445:Atomoxetine Hydrochloride; D006632:Histamine