Effects Of Noradrenergic Stimulation Research Articles

(Lack of) Effects of noradrenergic stimulation on human working memory performance

RationaleWorking memory depends on prefrontal cortex functioning, which is particularly sensitive to levels of noradrenaline. Studies in non-human primates have shown that modest levels of noradrenaline improve working memory, and that higher levels of noradrenaline impair working memory performance. However, research in humans provided inconsistent findings concerning noradrenergic effects on working memory.ObjectiveThe present study aimed at assessing dose-dependent effects of yohimbine, an alpha-2 adrenoceptor antagonist, on working memory performance in healthy humans. We further aimed to explore a potential interactive effect between noradrenergic arousal and lack of control over aversive events on working memory performance.MethodsWe used a double-blind, fully crossed, placebo-controlled, between-subject design. Participants (N = 121) performed an adaptive n-back task before and after oral administration of either a placebo, 20 mg, or 40 mg yohimbine and a manipulation of controllability, during which participants could either learn to avoid electric shocks (controllability groups), had no instrumental control over shock administration (uncontrollability groups), or did not receive any shocks (no-shock control group).ResultsWhile no significant results of noradrenergic stimulation through yohimbine were obtained using conventional frequentist analyses, additional Bayesian analyses provided strong evidence for the absence of an association between pharmacological treatment and working memory performance. We further observed no effect of controllability and no interaction between noradrenergic stimulation and the manipulation of controllability.ConclusionsOur results suggest that noradrenergic stimulation through yohimbine does not affect (non-spatial) working memory in healthy human participants.

Effects of Noradrenergic Stimulation Upon Context-Related Extinction Learning Performance and BOLD Activation in Hippocampus and Prefrontal Cortex Differ Between Participants Showing and Not Showing Renewal.

While the neural structures mediating context-related renewal of extinction are well established, the neurotransmitter systems processing renewal remain elusive. Noradrenergic stimulation before extinction improved learning, but did not alter renewal. Since context processing already during initial conditioning can influence renewal, in this fMRI study we investigated how noradrenergic stimulation by a single dose of atomoxetine (ATO) before initial acquisition of a context-related predictive-learning task affects subsequent learning and renewal in humans. ATO participants showing contextual renewal (REN) exhibited a selective extinction learning deficit compared to placebo (PLAC) and ATO participants lacking renewal (ATO NoREN), probably owing to formation of more stable associations during acquisition. New learning and retrieval during the extinction phase as well as initial acquisition were unimpaired. In ATO REN, higher activation in right inferior frontal gyrus (iFG) during acquisition may have supported the formation of more stable associations, while reduced activation in hippocampus and left iFG during extinction was associated with impaired context encoding and response inhibition. During recall, ATO REN showed reduced overall context-dependent renewal associated with higher activation in medial PFC and right hippocampus. The results demonstrate the importance of noradrenergic processing in inferior frontal cortex and hippocampus for human extinction learning, but not necessarily initial conditioning. Since an identical atomoxetine treatment evoked diverging blood-oxygen level dependent (BOLD) activation patterns in REN and NoREN participants, the effect is presumably related to the participants’ preferred processing strategies that may have recruited differentially interconnected networks in which noradrenergic stimulation produced diverging consequences. In the ATO REN group, probably an additive effect of their preferred processing strategy, which pre-activated the noradrenergic system, and the experimental treatment caused a shift beyond the optimal working range of the noradrenergic system, thus modulating BOLD activation in a way that impaired extinction learning and recall.

Effects of noradrenergic stimulation on memory in patients with major depressive disorder

Major depressive disorder (MDD) has been associated with alterations in the noradrenergic system and impaired memory function. In turn, enhanced memory function has been associated with noradrenergic stimulation. In this study, we examined whether noradrenergic stimulation would differentially improve memory function in patients with MDD and healthy controls. In a placebo-controlled crossover study, 20 patients with MDD and 18 age- and sex-matched healthy controls received either placebo or 5 mg of yohimbine, an alpha-2-adrenoceptor antagonist that causes increased noradrenergic activity, orally before memory testing. A word list paradigm was used to test memory consolidation. Furthermore, the autobiographical memory test assessing memory retrieval and a working memory test were administered. Salivary alpha-amylase and blood pressure were measured. Yohimbine improved memory consolidation (word list learning) across groups (main effect of yohimbine: p = 0.05). This effect was more prominent in depressed patients compared with controls (post hoc t-test: MDD p = 0.01, controls p = 0.77). Memory retrieval (autobiographical memory specificity) and working memory were not affected by yohimbine. Across groups, yohimbine administration resulted in an increase in blood pressure and alpha-amylase. In sum, these results further support the hypothesis that noradrenergic stimulation enhances memory consolidation. The mechanism by which yohimbine leads to stronger memory consolidation in depressed patients compared with healthy controls remains to be elucidated.

Effects of noradrenergic stimulation of the medial and lateral hypothalamus on cardiovascular responses

Summary Microinjections of noradrenaline into the medial hypothalamus of anaesthetized normotensive rats elicited hypotensive and hypertensive effects. Noradrenergic stimulation of the dorsomedial nucleus of the hypothalamus caused a drop in arterial pressure and heart rate, which was abolished by previous injection of phentolamine but not by previous injection of propranolol. Noradrenaline injected into the ventromedial nucleus caused an increase in blood pressure and heart rate, which was blocked by propranolol but not by phentolamine. Microinjection of noradrenaline into the lateral hypothalamic area elicited tachycardia and a hypertensive response, both abolished by phentolamine, but not by propranolol.