title: Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine.
abstract: Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Tzavara
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: C D
authors.initials: CD
authors.lastname: Overshiner
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
authors.forename: K W
authors.initials: KW
authors.lastname: Perry
authors.forename: M
authors.initials: M
authors.lastname: Wolff
authors.forename: D L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: J M
authors.initials: JM
authors.lastname: Witkin
authors.forename: G G
authors.initials: GG
authors.lastname: Nomikos
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008774:Methylphenidate / Q000494:pharmacology; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010364:Pattern Recognition, Visual / Q000187:drug effects*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000077593:Reboxetine; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D009025:Morpholines; D011437:Propylamines; D011954:Receptors, Dopamine; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride; D000077593:Reboxetine; D000109:Acetylcholine; D009638:Norepinephrine