Desipramine Modulation of α-, γ-Synuclein, and the Norepinephrine Transporter in an Animal Model of Depression
Desipramine Modulation of α-, γ-Synuclein, and the Norepinephrine Transporter in an Animal Model of Depression
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DOI：
10.1038/npp.2008.146
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发表时间：
2009-03-01
影响因子：
7.6
通讯作者：
Sidhu, Anita
中科院分区：
文献类型：
--
作者：
Jeannotte, Alexis M.;McCarthy, John G.;Sidhu, Anita
抑郁症的潜在机制仍然难以捉摸。我们之前确定α-突触核蛋白（α-Syn）以依赖于其与微管（MT）相互作用的方式调节去甲肾上腺素转运蛋白（NET）的活性和运输。在这里，我们试图确定 α-Syn 或其他突触核蛋白家族成员、β-突触核蛋白 (beta-Syn) 和 γ-突触核蛋白 (gamma-Syn) 是否调节抑郁症动物模型 Wistar-Kyoto (WKY) 大鼠中的 NET 活性。 NET 选择性抗抑郁药地昔帕明 (DMI) 长期给予 WKY 大鼠和未表现出抑郁样行为的远交品系 Wistar 大鼠，持续 14 天。在强迫游泳测试中，这种药物疗法使 WKY 大鼠的行为显着改善，但对 Wistar 大鼠却没有。在 WKY 大鼠中，γ-Syn 过度表达，但在 DMI 治疗后有所减少。与此同时，DMI 导致额叶皮质中的 alpha-Syn 和 NET 增加。 WKY 大鼠的额叶皮层突触体对诺考达唑不敏感，诺考达唑是一种促进 MT 不稳定的化合物。然而，在用 DMI 处理的 WKY 中，诺考达唑诱导 [H-3]-NE 摄取增加。这一趋势在 Wistars 中得到了逆转。这些 DMI 诱导的变化背后是突触核蛋白和 NET 与微管蛋白之间蛋白质相互作用的改变。这些结果首次表明α-Syn或γ-Syn与抑郁症的病理生理学有关，并表明靶向突触核蛋白可能为抑郁症提供新的治疗选择。
The mechanisms underlying depression remain elusive. We previously determined that alpha-synuclein (alpha-Syn) modulates the activity and trafficking of the norepinephrine transporter (NET) in a manner that is dependent on its interactions with microtubules (MTs). Here we sought to determine if alpha-Syn, or the other synuclein family members, beta-synuclein (beta-Syn) and gamma-synuclein (gamma-Syn), modulate NET activity in an animal model of depression, the Wistar-Kyoto (WKY) rat. The NET-selective antidepressant desipramine (DMI) was chronically administered for 14 days to WKY rats and the strain from which it was outbred that does not show depressive-like behavior, the Wistar rat. This drug regimen induced significant behavioral improvements in the WKY, but not the Wistar rat, in the forced swim test. In WKY rats there was an overexpression of gamma-Syn which was reduced following DMI treatment. In parallel, DMI caused an increase in both alpha-Syn and NET in the frontal cortex. Frontal cortex synaptosomes from WKY rats were not sensitive to nocodazole, a compound that promotes MT destabilization. However, in WKYs treated with DMI, nocodazole induced an increase in [H-3]-NE uptake. This trend was reversed in Wistars. Underlying these DMI-induced changes were alterations in the protein interactions between the synucleins and NET with the tubulins. These results are the first to implicate alpha-Syn or gamma-Syn in the pathophysiology of depression and suggest that targeting synucleins may provide a new therapeutic option for depression.