Dose-dependent effect of intracerebroventricular injection of ouabain on the phosphorylation of the MEK1/2-ERK1/2-p90RSK pathway in the rat brain related to locomotor activity.
Intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, induced behavioral changes in rats, a putative animal model for bipolar disorder. The binding of ouabain to Na-K ATPase is known to affect signaling molecules in vitro such as extracellular signal-regulated kinase1/2 (ERK1/2). Although ERK has been suggested to be related to the behavioral alterations induced by various psychotomimetics, the effect of ouabain on ERK in the brain related to behavioral changes has not been examined. After ICV injection of ouabain in rats, we investigated changes in the phosphorylation of mitogen-activated protein kinase kinase1/2 (MEK1/2), ERK1/2, and p90 ribosomal s6 kinase (p90RSK) in rat striatum, frontal cortex, and hippocampus along with changes in locomotor activity. Ouabain induced the following biphasic dose-dependent changes in locomotor activity: no change with 10(-6) M, a statistically significant decrease with 10(-5) M, no change with 10(-4) M, and a statistically significant increase with 0.5x10(-3) and 10(-3) M. The phosphorylation level of MEK1/2, ERK1/2, and p90RSK in rat striatum showed dose-dependent changes similar to those observed in locomotor activity with relatively high correlation. The phosphorylation of these molecules in rat frontal cortex and hippocampus also changed in a similar dose-dependent pattern. Taken together, ouabain induced biphasic dose-dependent changes in locomotor activity and the phosphorylation of the ERK1/2 pathway. These findings suggest a possible relationship between ouabain-induced behavioral changes and ERK activity in the brain and suggest an important role of ERK in regulating locomotor activity and mood state.
Kim
Se Hyun
SH
Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Yu
Hyun-Sook
HS
Park
Hong Geun
HG
Jeon
Won Je
WJ
Song
Joo Yun
JY
Kang
Ung Gu
UG
Ahn
Yong Min
YM
Lee
Young Han
YH
Kim
Yong Sik
YS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D010042:Ouabain; D048049:Extracellular Signal-Regulated MAP Kinases