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

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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.