diacylglycerol kinase β knockout mice exhibit attention-deficit behavior and an abnormal response on methylphenidate-induced hyperactivity二酰基甘油激酶β基因敲除小鼠表现出注意力methylphenidate-induced多动症行为和异常反应.pdfVIP

Diacylglycerol Kinase b Knockout Mice Exhibit Attention- Deficit Behavior and an Abnormal Response on Methylphenidate-Induced Hyperactivity 1 1 1 1 1 Mitsue Ishisaka , Kenichi Kakefuda , Atsushi Oyagi , Yoko Ono , Kazuhiro Tsuruma , 1 2 1 Masamitsu Shimazawa , Kiyoyuki Kitaichi , Hideaki Hara * 1 Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan, 2 Department of Pharmacy, Gifu University Hospital, Gifu, Japan Abstract Background: Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKb is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. Previously, we demonstrated that DGKb knockout (KO) mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density), hyperactivity, reduced anxiety, and careless behavior. In the present study, we conducted further tests on DGKb KO mice in order to investigate the function of DGKb in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Methodology/Principal Findings: DGKb KO mice showed attention-deficit behavior in the object-based attention test and it was ameliorated by methylphenidate (MPH, 30 mg/kg, i.p.). In the open field test, DGKb KO mice displayed a decreased response to the locomotor stimulating effects of MPH (30 mg/kg, i.p.), but showed a similar response to an N-methyl-D- aspartate (NMDA) receptor antagonist, MK-801 (0.3 mg/kg, i.p.), when compared to WT mice. Examination of the phosph