FV 4 The influence of Ketamine on the locus coeruleus and the noradrenerg system – a randomized fMRI study

Background Ketamine and its potential antidepressant mechanism, which has been proposed to be related to the glutamatergic system of the brain, are of growing interest. Since ketamine modulates the norepinephrine transporter (NET), we investigated the influence of ketamine on the Locus coeruleus (LC), the brain area with the highest NET density, the source of the noradrenergic fibers and an arousal regulatory center identified on resting state fMRI. Methods We investigated the resting state functional connectivity (rs-fc) of the LC before and after subanesthetic ketamine in a double-blind, randomized, controlled, parallel design trial with 7T MRI. 75 young, healthy participants (mean age 26.04±5.375years) were examined. We additionally explored differences in the rs-fc associated with a common polymorphism in the NET gene. Results The rs-fc of LC with the thalamus decreased significantly after ketamine administration. Thalamic nuclei including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral nucleus bilaterally and the right centromedian nucleus were decoupled from the LC following ketamine infusion. This decrease in rs-fc differed between the NET polymorphism carriers. Furthermore, we revealed an increase in rs-fc from LC to the right TPJ after ketamine administration. Conclusions We revealed an influence of ketamine on the central noradrenergic pathway. Moreover, the results suggest a potential influence of ketamine on the attention network. These findings could explain components of ketamine side-effects and may contribute to understanding its antidepressive effect.