TASK-3 as a potential antidepressant target

被引：35

作者：

Gotter, Anthony L. ^{[1
]}

Santarelli, Vincent P. ^{[2
]}

Doran, Scott M. ^{[3
]}

Tannenbaum, Pamela L. ^{[1
]}

Kraus, Richard L. ^{[2
]}

Rosahl, Thomas W. ^{[4
]}

Meziane, Hamid ^{[6
]}

Montial, Marina ^{[6
]}

Reiss, Duane R. ^{[1
]}

Wessner, Keith ^{[3
]}

McCampbell, Alexander ^{[5
]}

Stevens, Joanne ^{[3
]}

Brunner, Joseph I. ^{[1
]}

Fox, Steven V. ^{[3
]}

Uebele, Victor N. ^{[2
]}

Bayliss, Douglas A. ^{[7
]}

Winrow, Christopher J. ^{[1
]}

Renger, John J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Neurosci, West Point, PA USA

[2] Merck Res Labs, Dept In Vitro Pharmacol, West Point, PA USA

[3] Merck Res Labs, Dept In Vivo Pharmacol, West Point, PA USA

[4] Merck Res Labs, Dept Exploratory & Translat Sci, West Point, PA USA

[5] Merck Res Labs, Dept Mol Biomarkers, West Point, PA USA

[6] Mouse Clin Inst, Strasbourg, France

[7] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22903 USA

来源：

BRAIN RESEARCH | 2011年 / 1416卷

基金：

美国国家卫生研究院;

关键词：

Kcnk9; TASK-3; Sleep; Polysomnography; Major depressive disorder; Circadian; DEPRESSION-RESISTANT PHENOTYPE; BACKGROUND POTASSIUM CHANNEL; K+ CHANNELS; ELECTROCONVULSIVE-THERAPY; RESPIRATORY NEURONS; REM-SLEEP; RAT; MICE; PH; ANESTHETICS;

D O I：

10.1016/j.brainres.2011.08.021

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Modulation of TASK-3 (Kcnk9) potassium channels affect neurotransmitter release in thalamocortical centers and other sleep-related nuclei having the capacity to regulate arousal cycles and REM sleep changes associated with mood disorders and antidepressant action. Circumstantial evidence from this and previous studies suggest the potential for TASK-3 to be a novel antidepressant therapeutic target; TASK-3 knock-out mice display augmented circadian amplitude and exhibit sleep architecture characterized by suppressed REM activity. Detailed analysis of locomotor activity indicates that the amplitudes of activity bout duration and bout number are augmented in TASK-3 mutants well beyond that seen in wildtypes, findings substantiated by amplitude increases in body temperature and EEG recordings of sleep stage bouts. Polysomnographic analysis of TASK-3 mutants reveals increases in nocturnal active wake and suppressed REM sleep time while increased slow wave sleep typifies the inactive phase, findings that have implications for the cognitive impact of reduced TASK-3 activity. In direct measures of their resistance to despair behavior, TASK-3 knock-outs displayed significant decreases in immobility relative to wildtype controls in both tail suspension and forced swim tests. Treatment of wildtype animals with the antidepressant Fluoxetine markedly reduced REM sleep, while leaving active wake and slow wave sleep relatively intact. Remarkably, these effects were absent in TASK-3 mutants indicating that TASK-3 is either directly involved in the mechanism of this drug's action, or participates in parallel pathways that achieve the same effect. Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action. (C) 2011 Published by Elsevier B.V.

引用

页码：69 / 79

页数：11

共 46 条

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Electroconvulsive shock alters the rat overt rhythms of motor activity and temperature without altering the circadian pacemaker [J].