Essential Role of Dopamine D₂Receptor in the Maintenance of Wakefulness, But Not in Homeostatic Regulation of Sleep, in Mice

Abstract

Dopamine (DA) and its D 2 receptor (R) are involved in cognition, reward processing, and drug addiction. However, their roles in sleep-wake regulation remain unclear. Herein we investigated the role of D 2 R in sleep-wake regulation by using D 2 R knock-out (KO) mice and pharmacological manipulation. Compared with WT mice, D 2 R KO mice exhibited a significant decrease in wakefulness, with a concomitant increase in non-rapid eye movement (non-REM, NREM) and REM sleep and a drastic decrease in the low-frequency (0.75-2 Hz) electroencephalogram delta power of NREM sleep, especially during the first 4 h after lights off. The KO mice had decreased mean episode duration and increased episode numbers of wake and NREM sleep, many stage transitions between wakefulness and NREM sleep during the dark period, suggesting the instability of the wake stage in these D 2 R KO mice. When the KO mice were subjected to a cage change or an intraperitoneal saline injection, the latency to sleep in the KO mice decreased to half of the level for WT mice. The D 2 R antagonist raclopride mimicked these effects in WT mice. When GBR12909, a dopamine transport inhibitor, was administered intraperitoneally, it induced wakefulness in WT mice in a dose-dependent manner, but its arousal effect was attenuated to one-third in the D 2 R KO mice. However, these 2 genotypes showed an identical response in terms of sleep rebound after 2, 4, and 6 h of sleep deprivation. These results indicate that D 2 R plays an essential role in the maintenance of wakefulness, but not in homeostatic regulation of NREM sleep.

Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice

“…Recent pharmacological and gene-targeting studies suggest possible mechanisms involved. Dopamine antagonists inhibit the sleep latency increase caused by cage changes (23). Similarly, dopamine D2 receptor knockout mice do not exhibit longer sleep latencies after exposure to new environments (23,24).…”

“…Dopamine antagonists inhibit the sleep latency increase caused by cage changes (23). Similarly, dopamine D2 receptor knockout mice do not exhibit longer sleep latencies after exposure to new environments (23,24). Furthermore, mice with histamine deficiency also fail to exhibit prolonged sleep latencies during CC manipulation (25).…”

Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias

“…24) Dopamine D 2 receptor, which is co-expressed with the adenosine A 2A receptor, was also reported to play a role in the maintenance of wakefulness after caffeine administation. 24,25) In contrast, ephedrine alkaloids are known to express their pharmacological actions via the α-and β-adrenergic receptors, and are reported to induce release of endogenous catecholamines, such as noradrenaline and dopamine, indirectly and to prevent their neuronal reuptake. 26) Noradrenaline is one of the most abundant neurotransmitters in the central and peripheral nervous systems, and is implicated in many aspects of physiology and behavior, including cognition, attention, reward, locomotion, and arousal.…”

Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors

“…The EEG/EMG signals were amplified and filtered (EEG,EMG,, then digitized at a sampling rate of 128 Hz and recorded using SLEEPSIGN software (KISSEI COMTEC CO., LTD. Japan) as described elsewhere (Qu et al, 2008(Qu et al, , 2010. The vigilance states were automatically classified offline in 4-second epochs into rapid eye movement (REM) sleep, NREM sleep, and wakefulness by SLEEPSIGN, according to the standard criteria .…”