Abstract
Ethanol has extensive effects on sleep and daytime alertness, causing premature disability and death. Adenosine, as a potent sleep-promoting substance, is involved in many cellular and behavioral responses to ethanol. However, the mechanisms of hypnotic effects of ethanol remain unclear. In this study, we investigated the role of adenosine in ethanol-induced sleep using C57BL/6Slac mice, adenosine A2A receptor (A2AR) knockout mice, and their wild-type littermates. The results showed that intraperitoneal injection of ethanol (3.0 g/kg) at 21:00 decreased the latency to non-rapid eye movement (NREM) sleep and increased the duration of NREM sleep for 5 h. Ethanol dose-dependently increased NREM sleep, which was consistent with decreases in wakefulness in C57BL/6Slac mice compared with their own control. Caffeine (5, 10, or 15 mg/kg), a nonspecific adenosine receptor antagonist, dose-dependently and at high doses completely blocked ethanol-induced NREM sleep when administered 30 min prior to (but not after) ethanol injection. Moreover, ethanol-induced NREM sleep was completely abolished in A2AR knockout mice compared with wild-type mice. These findings strongly indicate that A2AR is a key receptor for the hypnotic effects of ethanol, and pretreatment of caffeine might be a strategy to counter the hypnotic effects of ethanol.
Highlights
Ethanol is one of the most highly abused psychoactive compounds worldwide[1,2]
A2A receptor (A2AR) WT mice showed an increase in duration of non-rapid eye movement (NREM) sleep, but A2AR KO mice showed no change in time spent in NREM sleep
The mouse treated with ethanol spent more time in NREM sleep compared with their own control
Summary
Ethanol is one of the most highly abused psychoactive compounds worldwide[1,2]. It produces a variety of acute and chronic effects[3], which have a significant socio-economic impact on the individuals, their families, and society. Extensive clinical studies have documented that acute ethanol has a profound impact on sleep[4,6], and acute discontinuation of alcohol in alcoholics results in severe disturbance of sleep architecture[6,7,8]. The role of A2AR in ethanol-induced hypnotic effects is still in debate Caffeine, another widely used psychoactive compound[31], binds A1R and A2AR with similar affinity as a receptor antagonist. Other studies have been unable to confirm these results[36,37] It is unclear whether caffeine can block ethanol-induced hypnotic effects. A2AR WT mice showed an increase in duration of NREM sleep, but A2AR KO mice showed no change in time spent in NREM sleep These findings indicate that A2AR plays an important role in the hypnotic effects of ethanol. Understanding the molecular mechanism underlying the hypnotic effects of ethanol may provide new therapeutic approaches for treating alcoholism and blocking acute behavioral impairment due to ethanol
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