Program

PO3-1-73

Prostaglandin E receptor subtype EP1 deficiency elicits AD/HD-like behavior correlated with a dysfunction of dopamine D1 receptor-ERK signaling in the prefrontal cortex

[Speaker] Akihiro Mouri:1,8
[Co-author] Tomoyuki Furuyashiki:2, Kazuo Kunisawa:3, Yasuko Yamamoto:4, Kiyofumi Yamada:5,8, Yukihiro Noda:6,8, Kuniaki Saito:4,8, Shu Narumiya:7, Toshitaka Nabeshima:3,8
1:Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Science, Japan, 2:Division of Pharmacology, Kobe University Graduate School of Medicine, Japan, 3:Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science., Japan, 4:Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Science., Japan, 5:Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Japan, 6:Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, Japan, 7:Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan, 8:Japanese Drug Organization of Appropriate Use and Research, Japan

[Background] Attention deficit/hyperactivity disorder (AD/HD) is characterized by inattention, hyperactivity and impulsivity and often persists into adulthood. Dysfunction of the dopaminergic systems in the prefrontal cortex is considered to be the pathophysiology of ADHD. Prostaglandin E2 plays key roles in multiple brain functions related to stress and psychostimulant response via modulating dopaminergic nervous system. Here, we clarified a novel role of prostaglandin E receptor subtype EP1 in emotional and cognitive functions in AD/HD.
[Methods] EP1 knockout mice were subjected sequence of behavioral tests. To investigate the dopaminergic functions in EP1 knock out mice, we examined learning-associated and dopamine D1 receptor-activated phosphorylation of extracellular signaling-regulated kinase (ERK) by Western blotting analysis and the ability of extracellular dopamine release by in vivo microdialysis analysis.
[Results] EP1 knockout mice showed normal circadian rhythm, but AD/HD-like behavior such as impulsiveness in cliff avoidance test, decrease in sociality in social interaction test, and an impairment of object recognition memory in novel object recognition test. The EP1 knockout mice displayed impairments of learning -associated and dopamine D1 receptor-activated phosphorylation of ERK in the prefrontal cortex. Administration of methylphenidate and atomoxetine reversed these AD/HD-like behaviors and impairment of learning -associated phosphorylation of ERK in EP1 knockout mice. The dopamine release induced by high potassium in the prefrontal cortex of EP1 knockout mice was normal.
[Conclusions] EP1 knock out mice showed the behavioral changes with good face validity as an animal model for AD/HD through the prefrontal cortical dysfunction of dopamine D1 receptor-ERK signaling. Pharmacological responses to anti-AD/HD medications in behavioral tasks suggest that EP1 knockout mice have the potential to be a model with predictive validity for assessments of new therapeutics for AD/HD.

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