Abstracts

Abstract

Objectives: Common variation in genes regulating dopaminergic neurotransmission, including catechol-O-methyl-transferase (COMT) and dopamine transporter (DAT), impact on rest-activity patterns (Valomon et al., 2014) and neurophysiological markers of sleep-wake regulation (Holst et al., 2014). COMT degrades dopamine in prefrontal cortex; it can be inhibited by tolcapone, used in Parkinson therapy. To examine a causal relationship between dopaminergic neurotransmission and the consequences of sleep loss, we investigated the effects of tolcapone on mood and working memory in sleep-deprived volunteers. Methods: 2 x 100 mg tolcapone were administered to 12 adult young men after 11 and 23 h of 40 h prolonged wakefulness (randomized, double-blind, placebo-controlled, cross-over design). The Karolinska Sleepiness Scale, the Profile of Mood States and a visual 2-back task were regularly conducted. Repeated measure mixed-model analyses of variance were applied. Results: Symptoms of sleepiness, fatigue, irritability, and depression increased with time awake, while speed and accuracy on the 2-back task decreased. Compared to placebo, tolcapone tended to lower fatigue and irritability (P = 0.05 and P = 0.08). Moreover, it improved response speed (P < 0.03), yet not accuracy, on the 2-back task. Conclusions: These preliminary results of an ongoing study indicate that pharmacological inhibition of COMT improves impaired mood states and working memory after sleep deprivation, suggesting that altered dopaminergic signaling contributes to these consequences of sleep loss in healthy volunteers. The observed large inter-individual differences in the effects of tolcapone may reflect different genotypes of the functional Val158Met polymorphism of COMT.