Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide

Y Shibasaki; A Hayata-Takano; K Hazama; T Nakazawa; N Shintani; A Kasai; K Nagayasu; R Hashimoto; M Tanida; T Katayama; S Matsuzaki; K Yamada; M Taniike; Y Onaka; Y Ago; J A Waschek; K Köves; D Reglődi; A Tamas; T Matsuda; A Baba; H Hashimoto

doi:10.1016/j.neuroscience.2015.03.062

Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide

Neuroscience. 2015 Jun 25:297:95-104. doi: 10.1016/j.neuroscience.2015.03.062. Epub 2015 Apr 1.

Authors

Y Shibasaki¹, A Hayata-Takano², K Hazama¹, T Nakazawa³, N Shintani¹, A Kasai¹, K Nagayasu³, R Hashimoto⁴, M Tanida⁵, T Katayama⁶, S Matsuzaki⁷, K Yamada⁸, M Taniike⁹, Y Onaka¹⁰, Y Ago¹¹, J A Waschek¹², K Köves¹³, D Reglődi¹⁴, A Tamas¹⁴, T Matsuda¹⁵, A Baba¹⁶, H Hashimoto¹⁷

Affiliations

¹ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
² 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.
³ iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
⁴ 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.
⁵ Department of Physiology II, Kanazawa Medical University, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
⁶ 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.
⁷ 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.
⁸ Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ Department of Human Morphology and Developmental Biology, Semmelweis University, Tűzoltó utca 58, 1094 Budapest, Hungary.
¹⁴ Department of Anatomy, PTE-MTA "Lendulet" PACAP Research Team, Medical School, University of Pecs, Szigeti 12, 7624 Pecs, Hungary.
¹⁵ 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.
¹⁶ School of Pharmacy, Hyogo University of Health Sciences, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
¹⁷ 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.

PMID: 25841321
DOI: 10.1016/j.neuroscience.2015.03.062

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.

Keywords: atomoxetine (ATX); attention-deficit/hyperactivity disorder (ADHD); hyperactivity; memory; pituitary adenylate cyclase-activating polypeptide (PACAP); prepulse inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acoustic Stimulation
Adrenergic Uptake Inhibitors / therapeutic use*
Analysis of Variance
Animals
Atomoxetine Hydrochloride / therapeutic use*
Biogenic Monoamines / metabolism
Cognition Disorders / drug therapy*
Cognition Disorders / genetics
Dose-Response Relationship, Drug
Exploratory Behavior / drug effects
Hyperkinesis / drug therapy*
Hyperkinesis / etiology
Memory Disorders / drug therapy*
Memory Disorders / genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Microdialysis
Pituitary Adenylate Cyclase-Activating Polypeptide / deficiency*
Pituitary Adenylate Cyclase-Activating Polypeptide / genetics
Prepulse Inhibition / drug effects*
Recognition, Psychology / drug effects

Substances

Adrenergic Uptake Inhibitors
Biogenic Monoamines
Pituitary Adenylate Cyclase-Activating Polypeptide
Atomoxetine Hydrochloride