Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects
Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects
复制标题
DOI：
10.1038/mp.2011.92
复制
发表时间：
2012-06-01
影响因子：
11
通讯作者：
Artigas, F.
中科院分区：
文献类型：
--
作者：
Bortolozzi, A.;Castane, A.;Artigas, F.
抑郁症是世界范围内的一个主要健康问题。大多数处方抗抑郁药，选择性5-羟色胺再摄取抑制剂（SSRI）显示有限的疗效和延迟起效，部分原因是由于SSRI在中缝核中产生的过量细胞外5-羟色胺（5-HT）激活体树突5-HT 1A-自身受体。同样，5-HT 1A受体（5-HT 1AR）基因多态性导致5-HT 1A自身受体高表达，增加抑郁症易感性，降低治疗反应。在这项研究中，我们报告了一种新的治疗策略的基础上管理的小干扰RNA（siRNA），以急性抑制5-HT 1A-自身受体介导的负反馈机制。我们通过将靶向5-HT 1A受体mRNA的siRNA与SSRI舍曲林共价结合，以将其集中在富含5-羟色胺转运体（SERT）位点的5-羟色胺轴突中，开发了缀合siRNA（C-1A-siRNA）。脑室内（i. c. v.）向小鼠输注C-1A-siRNA导致其在5-羟色胺神经元中的选择性积累。在强迫游泳和悬尾实验中，这引起了显着的抗焦虑样作用，但在高架十字迷宫中并不影响焦虑样行为。同时，C-1A-siRNA给药显著降低5-HT 1A-自身受体表达并抑制8-OH-DPAT诱导的体温降低（小鼠中的突触前5-HT 1AR效应），而不影响海马和前额皮质中的突触后5-HT 1AR表达。此外，i. c. v. C-1A-siRNA输注增强了前额叶皮层中氟西汀诱发的细胞外5-羟色胺的增加，达到5-HT 1AR敲除小鼠中观察到的水平。有趣的是，鼻内C-1A-siRNA给药产生了相同的效果，从而为C-1A-siRNA的治疗用途开辟了道路。因此，C-1A-siRNA代表了一种治疗情绪障碍的新方法，可以单独使用或与SSRI联合使用。Molecular Psychiatry（2012）17，612-623; doi：10.1038/mp.2011.92; 2011年8月2日在线发表
Depression is a major health problem worldwide. Most prescribed anti-depressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT1A-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT1A receptor (5-HT1AR) gene polymorphisms leading to high 5-HT1A-autoreceptor expression increase depression susceptibility and decrease treatment response. In this study, we report on a new treatment strategy based on the administration of small-interfering RNA (siRNA) to acutely suppress 5-HT1A-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT1A receptor mRNA with the SSRI sertraline in order to concentrate it in serotonin axons, rich in serotonin transporter (SERT) sites. The intracerebroventricular (i.c.v.) infusion of C-1A-siRNA to mice resulted in its selective accumulation in serotonin neurons. This evoked marked anti-depressant-like effects in the forced swim and tail suspension tests, but did not affect anxiety-like behaviors in the elevated plus-maze. In parallel, C-1A-siRNA administration markedly decreased 5-HT1A-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT1AR effect in mice) without affecting post-synaptic 5-HT1AR expression in hippocampus and prefrontal cortex. Moreover, i.c.v. C-1A-siRNA infusion augmented the increase in extracellular serotonin evoked by fluoxetine in prefrontal cortex to the level seen in 5-HT1AR knockout mice. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders as monotherapy or in combination with SSRI. Molecular Psychiatry (2012) 17, 612-623; doi:10.1038/mp.2011.92; published online 2 August 2011