Department of Neurochemistry and Neuropharmacology, IIBB - CSIC - IDIBAPS, Barcelona, Spain.
Mol Psychiatry. 2012 Jun;17(6):612-23. doi: 10.1038/mp.2011.92. Epub 2011 Aug 2.
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-HT(1A)-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT(1A) receptor (5-HT(1A)R) gene polymorphisms leading to high 5-HT(1A)-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-HT(1A)-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT(1A) 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-HT(1A)-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT(1A)R effect in mice) without affecting post-synaptic 5-HT(1A)R 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-HT(1A)R 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.
抑郁症是全球范围内的一个主要健康问题。大多数处方抗抑郁药，即选择性 5-羟色胺再摄取抑制剂（SSRIs），显示出有限的疗效和起效延迟，部分原因是 SSRI 在中缝核中产生的过量细胞外 5-羟色胺（5-HT）激活了 somatodendritic 5-HT（1A）-自受体。同样，导致高 5-HT（1A）-自受体表达的 5-HT（1A）受体（5-HT（1A）R）基因多态性增加了抑郁症的易感性并降低了治疗反应。在这项研究中，我们报告了一种新的治疗策略，该策略基于小干扰 RNA（siRNA）的给药，以急性抑制 5-HT（1A）-自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，开发了一种缀合 siRNA（C-1A-siRNA），以便将其集中在富含 5-羟色胺转运体（SERT）位点的 5-羟色胺轴突中。将 C-1A-siRNA 脑室内（i.c.v.）输注到小鼠中会导致其选择性地积聚在 5-羟色胺神经元中。这在强迫游泳和悬尾试验中引起了明显的抗抑郁样作用，但不会影响高架十字迷宫中的焦虑样行为。平行地，C-1A-siRNA 给药显着降低了 5-HT（1A）-自受体的表达，并抑制了 8-OH-DPAT 诱导的体温降低（小鼠中的前突触 5-HT（1A）R 作用），而不影响海马和前额叶皮质中的突触后 5-HT（1A）R 表达。此外，i.c.v. C-1A-siRNA 输注增强了氟西汀在额皮质中引起的细胞外 5-羟色胺的增加，使其达到 5-HT（1A）R 敲除小鼠的水平。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 代表了一种作为单一疗法或与 SSRI 联合治疗情绪障碍的新方法。
