title: Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shibasaki
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: a-hayata@phs.osaka-u.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Hayata-Takano
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hazama
authors.affiliation: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shintani
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kasai
authors.affiliation: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nagayasu
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Psychiatry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanida
authors.affiliation: Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Katayama
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsuzaki
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Pediatrics, Graduate School of Medicine, Osaka University Suita, Osaka 565-0871, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Taniike
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Onaka
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Semel Institute for Neuroscience and Human Behavior, Intellectual Development and Disabilities Research Center, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, Intellectual Development and Disabilities Research Center, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Waschek
authors.affiliation: Department of Human Morphology and Developmental Biology, Semmelweis University, Tűzoltó utca 58, 1094 Budapest, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Köves
authors.affiliation: Department of Anatomy, PTE-MTA "Lendulet" PACAP Research Team, Medical School, University of Pecs, Szigeti 12, 7624 Pecs, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Reglődi
authors.affiliation: Department of Anatomy, PTE-MTA "Lendulet" PACAP Research Team, Medical School, University of Pecs, Szigeti 12, 7624 Pecs, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Tamas
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: School of Pharmacy, Hyogo University of Health Sciences, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Baba
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: hasimoto@phs.osaka-u.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Hashimoto
mesh_terms: D000161:Acoustic Stimulation; D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000069445:Atomoxetine Hydrochloride / Q000627:therapeutic use*; D015306:Biogenic Monoamines / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006948:Hyperkinesis / Q000188:drug therapy* / Q000209:etiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency* / Q000235:genetics; D065808:Prepulse Inhibition / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D000069445:Atomoxetine Hydrochloride
keywords: atomoxetine (ATX); attention-deficit/hyperactivity disorder (ADHD); hyperactivity; memory; pituitary adenylate cyclase-activating polypeptide (PACAP); prepulse inhibition