Bahi Amine, Dreyer Jean-Luc
Department of Anatomy, Tawam Medical Campus, United Arab Emirates University, Al Ain, United Arab Emirates.
Division of Biochemistry, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
Behav Brain Res. 2019 Feb 1;359:104-115. doi: 10.1016/j.bbr.2018.10.028. Epub 2018 Oct 24.
Many epidemiological and clinical studies have demonstrated a strong comorbidity between anxiety and depression, and a number of experimental studies indicates that the dopamine transporter (DAT) is involved in the pathophysiology of anxiety and depression. However, studies using laboratory animals have yielded inconclusive results. The aim of the present study was to examine the effects of DAT manipulation on anxiety- and depression-like behaviors in mice. For this purpose, animals were stereotaxically injected with DAT siRNA-expressing lentiviral vectors (siDAT) in the caudate putamen (CPu) or in the nucleus accumbens (Nacc) and the behavioral outcomes were assessed using the open-field (OF), elevated-plus maze (EPM), light-dark box (LDB), sucrose preference (SPT), novelty suppressed feeding (NSF), and forced-swim (FST) tests. The results showed that in the Nacc, but not in the CPu, siDAT increased the time spent at the center of the arena and decreased the number of fecal boli in the OF test. In the EPM and LDB tests, Nacc siDAT injection increased the entries and time spent on open arms, and increased the time spent in the light side of the box, respectively, suggesting an anxiolytic-like activity. In addition, siDAT, in the Nacc, induced significant antidepressant-like effects, evidenced by increased sucrose preference, shorter latency to feed in the NSF test, and decreased immobility time in the FST. Most importantly, Pearson's test clearly showed significant correlations between DAT mRNA in the Nacc with anxiety and depression parameters. Overall, these results suggest that low DAT levels, in the Nacc, might act as protective factors against anxiety and depression. Therefore, targeting DAT activity might be a very attractive approach to tackle affective disorders.
许多流行病学和临床研究已证实焦虑症和抑郁症之间存在很强的共病关系，并且一些实验研究表明多巴胺转运体（DAT）参与了焦虑症和抑郁症的病理生理过程。然而，使用实验动物的研究结果并不确定。本研究的目的是检验DAT操控对小鼠焦虑样和抑郁样行为的影响。为此，通过立体定位向动物的尾壳核（CPu）或伏隔核（Nacc）注射表达DAT小干扰RNA（siRNA）的慢病毒载体（siDAT），并使用旷场试验（OF）、高架十字迷宫试验（EPM）、明暗箱试验（LDB）、蔗糖偏好试验（SPT）、新奇抑制摄食试验（NSF）和强迫游泳试验（FST）评估行为结果。结果显示，在Nacc而非CPu中，siDAT增加了在旷场试验中在场地中心停留的时间，并减少了粪便颗粒的数量。在EPM试验和LDB试验中，向Nacc注射siDAT分别增加了进入开放臂的次数和在开放臂上停留的时间，以及在箱子亮侧停留的时间，表明具有抗焦虑样活性。此外，Nacc中的siDAT诱导了显著的抗抑郁样效应，表现为蔗糖偏好增加、在NSF试验中摄食潜伏期缩短以及在FST中不动时间减少。最重要的是，Pearson检验清楚地显示Nacc中DAT mRNA与焦虑和抑郁参数之间存在显著相关性。总体而言，这些结果表明Nacc中低水平的DAT可能是预防焦虑和抑郁的保护因素。因此，针对DAT活性可能是治疗情感障碍的一种非常有吸引力的方法。
