Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates tyrosine hydroxylase through extracellular signal-regulated kinase in rat striatum |
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Authors: | Yu Hyun Sook Kim Se Hyun Park Hong Geun Kim Yong Sik Ahn Yong Min |
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Institution: | a Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea b Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea c Brain Korea 21 Division of Human Life Science, Seoul National University College of Medicine, Seoul, Republic of Korea d Department of Psychiatry and Behavioral Science, Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea |
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Abstract: | Alteration in dopamine neurotransmission has been reported to be involved in the mania of bipolar disorder. Tyrosine hydroxylase (TH) is the rate-limiting enzyme that is crucial for dopamine biosynthesis, and its activity is tightly regulated by phosphorylation at multiple N-terminal serine residues. Previously, we have reported that intracerebroventricular (ICV) injection of ouabain, a selective Na/K-ATPase inhibitor, induces hyperactivity in rats that mimics manic symptoms related to the activation of extracellular signal-regulated protein kinase1/2 (ERK1/2), which plays crucial roles in the modulation of TH phosphorylation. In this study, we investigated the effects of ICV injection of ouabain on TH phosphorylation in rat striatum and the involvement of ERK1/2 in ouabain-induced TH activation. ICV ouabain induced an acute dose-dependent increase in locomotor activity and in TH phosphorylation in rat striatum. TH phosphorylation at Ser19 was significantly increased with 100, 500, and 1000 μM ouabain, and phosphorylation at Ser31 and Ser40 was significantly increased with 500 and 1000 μM. We also found that ICV pretreatment with U0126, a specific MEK1/2 inhibitor, attenuated the 1000 μM ouabain-induced increase in TH phosphorylation at Ser19, Ser31, and Ser40, as well as the hyperactivity of rats. Moreover, the increased phosphorylation of TH (Ser19, Ser31, and Ser40) was maintained until 8 h after single administration ouabain was accompanied by increased phosphorylation of ERK1/2 (Thr202/Tyr204) and p90RSK (Thr359/Ser363). These findings imply that TH activation of the ERK1/2 signal pathway could play an important role in ouabain-induced hyperactivity of rats, a mania model. |
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Keywords: | Na/K-ATPase Catecholamine Mitogen-activated protein kinase Locomotor activity Bipolar disorder |
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