A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment
A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment
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DOI：
10.1016/j.biopsych.2006.05.047
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发表时间：
2007-03-01
影响因子：
10.6
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
--
作者：
Duman, Catharine H.;Schlesinger, Lee;Duman, Ronald S.
背景：脑源性神经营养因子（BDNF）通过抗抑郁治疗在海马中上调，在啮齿动物抑郁行为模型中，集中给予BDNF可产生抗抑郁样作用。因此，bdnf调节的信号通路是研究抗抑郁机制的潜在目标。方法：我们研究了MAPK激酶（MEK）抑制在小鼠抑郁症行为模型中的作用，包括与抗抑郁药物的相互作用。我们还评估了杂合基因缺失对BDNF合并MEK抑制或应激的行为后果。结果：急性给药MEK抑制剂PD184161可产生抑郁样行为。PD184161阻断地西帕明和舍曲林在强迫游泳试验中的抗抑郁样作用，阻断地西帕明在悬尾试验中的作用。单独的BDNF杂合缺失并不影响强迫游泳试验中的行为，但当与低剂量MEK抑制剂或应激暴露联合使用时，会导致抑郁表型。结论：我们证明急性阻断MAPK信号会产生抑郁样表型，并阻断抗抑郁药的行为作用。我们还在BDNF杂合敲除小鼠中证明了一个确定的基因改变如何赋予对药理学或环境挑战的脆弱性，从而导致抑郁行为表型的例子。
Background: Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and centrally administered BDNF can produce antidepressant-like effects in rodent behavioral models of depression. BDNF-regulated signaling pathways are thus potential targets for investigation of antidepressant mechanisms.Methods: We examined the effects of inhibition of MAPK kinase (MEK) in mouse behavioral models for depression including interactions with effects of antidepressant drugs. We also assessed the behavioral consequences of a heterozygous gene deletion for BDNF combined with MEK inhibition or stress.Results: Acute administration of the MEK inhibitor PD184161 produced depressive-like behavior. PD184161 blocked the antidepressant-like effects of desipramine and sertraline in the forced swim test and blocked the effects of desipramine in the tail suspension test. Heterozygous deletion of BDNF alone did not influence behavior in the forced swim test but resulted in a depressive phenotype when combined with a low-dose MEK inhibitor or stress exposure.Conclusions: We demonstrate that acute blockade of MAPK signaling produces a depressive-like phenotype and blocks behavioral actions of antidepressants. We also demonstrate in BDNF heterozygous knockout mice an example of a how a defined genetic alteration can confer vulnerability to a pharmacologic or environmental challenge resulting in a depressive behavioral phenotype.