Dopaminergic Role in Regulating Neurophysiological Markers of Sleep Homeostasis in Humans

Abstract

While dopamine affects fundamental brain processes such as movement control, emotional responses, addiction, and pain, the roles for this neurotransmitter in regulating wakefulness and sleep are incompletely understood. Genetically modified animal models with reduced dopamine clearance exhibit hypersensitivity to caffeine, reduced-responsiveness to modafinil, and increased homeostatic response to prolonged wakefulness when compared with wild-type animals. Here we studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3Ј-UTR variable-number-tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter (DAT). Previous research demonstrated that healthy homozygous 10-repeat (10R/10R) allele carriers of this genetic variant have reduced striatal DAT protein expression when compared with 9-repeat (9R) allele carriers. Objective and subjective estimates of caffeine sensitivity were higher in 10R allele homozygotes than in carriers of the 9R allele. Moreover, caffeine and modafinil affected wakefulness-induced changes in functional bands (delta, sigma, beta) of rhythmic brain activity in wakefulness and sleep in a DAT1 genotype-dependent manner. Finally, the sleep deprivation-induced increase in well established neurophysiologic markers of sleep homeostasis, including slow-wave sleep, electroencephalographic slowwave activity (0.5-4.5 Hz), and number of low-frequency (0.5-2.0 Hz) oscillations in non-rapid-eye-movement sleep, was significantly larger in the 10R/10R genotype than in the 9R allele carriers of DAT1. Together, the data suggest that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans.

Assessment of subjective sleep quality in iron deficiency anaemia

“…Neuromodulation by the DA system plays an important role in sleep regulation, including the modulation of REM sleep quality, quantity, and timing 28,29 . Holst et al 30 , studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3′-UTR variable-number-tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter. Their findings suggested that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans.…”

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation

“…Moreover, genetically modified animals lacking a functional dopamine re-uptake transporter (DAT) exhibit prolonged wakefulness and shortened sleep2526272829. In humans, a variable-number-tandem-repeat (VNTR) polymorphism (SNP-ID: rs28363170) of the gene encoding DAT ( SLC6A3 or DAT1 ) modulates individual effects of sleep loss on sleep rebound and sensitivity to caffeine, as well as rewards and punishments3031. Homozygous ten-repeat allele (10R/10R) carriers of this polymorphism presumably have 15–20% reduced DAT protein expression compared to nine-repeat (9R) allele carriers3233.…”

“…Homozygous ten-repeat allele (10R/10R) carriers of this polymorphism presumably have 15–20% reduced DAT protein expression compared to nine-repeat (9R) allele carriers3233. Compared to the 9R carriers, 10R/10R homozygotes exhibits a clearly and more pronounced increase in sleep intensity after extended waking (as measured by EEG slow-wave activity [SWA] in non-rapid-eye-movement [NREM] sleep)30. This measure is the best established biomarker of increased sleep need after sleep loss34.…”

Sleep and Addictions

“…In one study, fruit flies carrying the Dat lo mutation, which reduces enzymatic clearance of dopamine, displayed a greater sleep rebound after sleep deprivation than did wildtype controls (Greenspan, Tononi, Cirelli, & Shaw, 2001). Similarly, Holst et al (2014) found that human homozygotic carriers of an allele of the dopamine transporter that reduces dopamine transporter availability (10R/10R, Costa, Riedel, Müller, Möller, & Ettinger, 2011) had a greater SWA rebound after sleep deprivation. It is yet to be determined whether this SWA rebound is associated with the downregulation of D2/D3 receptors (Volkow et al, 2012).…”