Effects of increased noradrenergic activity by yohimbine administration on learning and attention in patients with major depression disorder

应激在严重抑郁障碍(MDD)的发展和维持中起着重要作用。事实上，各种研究表明，MDD患者的生理应激调节系统，即下丘脑-垂体-肾上腺(HPA)轴和蓝斑-去甲肾上腺素(LC-NA)系统发生了适应不良的变化。在中央层面上，已经展示了LC-NA系统的变化。一些研究表明MDD患者的肾上腺素受体反应性(α2-肾上腺素能受体上调)发生了变化。尤其是在有早期生活创伤的MDD患者中，情况似乎更是如此。与HPA轴相比，LC-NA系统不仅影响生理应激反应，而且对认知功能也有中枢影响。事实上，NA对健康人的注意力、学习和记忆等认知功能的影响已经被证明。总而言之，NA似乎对巩固记忆有增强作用。尽管注意力和记忆等认知领域的缺陷是MDD的核心症状，但到目前为止，去甲肾上腺素系统和记忆过程的关系很少被研究。因此，我们的研究小组在第一项研究中调查了通过给予α2受体阻滞剂育亨宾来刺激去甲肾上腺素对不同记忆功能的影响。在那里，我们发现了记忆巩固的改善，与健康对照组相比，MDD患者的改善更加明显。此外，我们发现育亨宾促进了早期生活创伤的巩固改善。在这个项目中，我们的目标是首次调查通过给予α2受体阻滞剂育亨宾的去甲肾上腺素刺激在MDD患者中是否也比健康对照组在a)学习和b)注意力过程中有更明显的效果。因此，我们将使用Dot-Probe任务的一种情绪变体来研究a)注意过程，特别关注抑郁的消极偏见，以及b)使用恐惧条件反射范式的获得和消退过程。此外，我们还将调查早期生活创伤对这些关系的影响。因此，我们计划调查有和没有早期生活创伤的MDD患者。基于这些原因，我们计划调查40名MDD患者(20名有早期生活创伤)和40名健康对照(20名没有早期生活创伤；年龄、性别和教育状况匹配)。本研究结果将提高我们对MDD患者认知障碍和α2-肾上腺素能系统作用的理解，从而支持通过考虑这些关系来开发新的治疗策略。

Stress plays a major role in the development and maintenance of major depression disorder (MDD). Indeed, various studies demonstrated maladaptive changes in physiological stress regulation systems of MDD patients, i.e. in the hypothalamus-pituitary-adrenal (HPA) axis and the locus coeruleus-noradrenergic (LC-NA) system. On a central level, changes of the LC-NA system have been demonstrated. Several studies could show changes of the adrenoreceptor responsiveness (up-regulation of alpha2-adrenergic receptors) in MDD patients. This seems to be the case especially in MDD patients with early life traumata. Comparable to the HPA axis, the LC-NA system influences not only the physiological stress response, but has also central influence with effects on cognitive functions. Indeed, NA effects on cognitive functions such as attention, learning and memory have been demonstrated in healthy individuals. In summary, NA seems to have enhancing effects on memory consolidation. Even though deficits in cognitive domains such as attention and memory are core symptoms of MDD, the relationship of the noradrenergic system and memory processes has rarely been investigated so far. Therefore, our research group investigated in a first study the influence of noradrenergic stimulation via administration of the alpha2-receptor blocker yohimbine on different memory functions. There,, we found an improvement of memory consolidation that was even more pronounced in MDD patients compared to healthy controls. Additionally, we found associations of yohimbine triggered consolidation improvements to early life traumata.In this project, we aim to investigate for the first time, if noradrenergic stimulation via administration of the alpha2-receptor blocker yohimbine has also more pronounced effects in MDD patients compared to healthy controls for a) learning and b) attention processes. Therefore, we will examine a) attention processes using an emotional variant of the Dot-Probe-task with a special focus on the depressive negativity bias and b) acquisition and extinction processes using a fear conditioning paradigm. Additionally, we will investigate the influence of early life traumata on these relationships. Thus, we plan to investigate MDD patients with and without early life traumata.For these reasons, we plan to investigate 40 MDD patients (20 with/ 20 without early life traumata) and 40 healthy controls (20 with/ 20 without early life traumata; matched for age, sex and educational status) in a double-blind, placebo controlled, repeated measures design.Results of this study will improve our understanding of cognitive deficits and the role of alpha2-adrenergic system in MDD patients, and thus support the development of new therapeutic strategies by considering these relations.