Dept. Cell Biology & Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Neurosci Lett. 2013 Aug 26;548:38-43. doi: 10.1016/j.neulet.2013.05.076. Epub 2013 Jun 13.
Brain serotonin (5-HT) systems modulate emotional, motivational and cognitive processes. Mutations in the serotonin transporter (SERT) gene have been associated with susceptibility towards the development of several psychiatric disorders, both in humans and animal models. Present approach exploited a bilateral intra-hippocampus stereotaxic inoculation of lentiviruses, for enduring in vivo silencing of SERT. Control rats were bilaterally inoculated with heat-inactivated lentiviruses. These Lenti-SERT vectors were intended to eventually manipulate the neurotransmitter reuptake at synaptic level, thus enhancing tonic 5-HT transmission. We investigated whether such manipulation could induce behavioural alterations relevant to the modelling of ADHD, in particular symptoms of hyperactivity and impulsivity. Wistar rats were monitored for spontaneous home-cage locomotor activity and studied for impulsivity (Intolerance-to-Delay task). Results show that rats inoculated with Lenti-SERT vectors exhibited less pronounced circadian peaks of activity than controls. Moreover, Lenti-SERT compared to control rats exhibited a transient increase in choice for a delayed-larger reward over an immediate-small reward. This suggests that enhanced hippocampal serotonergic transmission produced a profile of restfulness and a decrease in cognitive impulsivity. This phenotype is consistent with available data both on 5-HT manipulations and hippocampal lesions. In conclusion, present findings may possibly disclose novel avenues towards the development of innovative therapeutical approaches for behavioural symptoms relevant to ADHD.
大脑中的 5-羟色胺（5-HT）系统调节情绪、动机和认知过程。在人类和动物模型中，5-羟色胺转运体（SERT）基因的突变与多种精神疾病的易感性有关。目前的方法利用双侧海马立体定位注射慢病毒，实现 SERT 的体内持续沉默。对照大鼠接受双侧热失活慢病毒接种。这些 Lenti-SERT 载体旨在最终操纵突触水平的神经递质再摄取，从而增强 5-HT 的紧张传递。我们研究了这种操作是否会导致与 ADHD 建模相关的行为改变，特别是多动和冲动症状。Wistar 大鼠在自发的家庭笼活动中进行监测，并进行冲动性（延迟容忍任务）研究。结果表明，与对照组相比，接种 Lenti-SERT 载体的大鼠的活动昼夜节律峰值不那么明显。此外，与对照组相比，Lenti-SERT 大鼠表现出对延迟较大奖励的选择增加，而不是即时较小奖励。这表明增强的海马 5-羟色胺能传递产生了一种安静的状态，并降低了认知冲动性。这种表型与 5-HT 操作和海马损伤的现有数据一致。总之，目前的发现可能为 ADHD 相关行为症状的创新治疗方法的开发开辟新途径。
