Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jun;49(4):299-310.
doi: 10.1016/j.alcohol.2014.07.019. Epub 2014 Nov 11.

Alcohol disrupts sleep homeostasis

Mahesh M Thakkar  1 , Rishi Sharma  2 , Pradeep Sahota  2
Affiliations
Review

Alcohol disrupts sleep homeostasis

Mahesh M Thakkar et al. Alcohol. 2015 Jun.

Abstract

Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired sleep homeostasis. In conclusion, we suggest that alcohol may disrupt sleep homeostasis to cause sleep disruptions.

Keywords: Adenosine; Alcohol dependence; Basal forebrain; Binge drinking; Cholinergic; Sleep deprivation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Alcohol has complex interactions with sleep.
Figure 2
Figure 2
A schematic sagittal view of a mammalian brain depicting neuronal systems mediating the ventral (blue) and dorsal (red) relays of the reticular activating system controlling cortical activation and behavioral arousal. Abbreviations: RAS = glutamatergic reticular activating system; LC = noradrenergic locus coeruleus; LDT and PPT = cholinergic laterodorsal and pedunculopontine tegmental nuclei; DR = serotonergic dorsal raphe; LH = orexinergic perifornical lateral hypothalamus; TMN = histaminergic tuberomammillary nucleus; BF = cholinergic basal forebrain.
Figure 3
Figure 3
The interaction of the circadian alerting signal and the homeostatic sleep drive in the regulation of sleep-wakefulness is described. During the day, an increasing circadian alerting signal counteracts accumulating sleep pressure to maintain wakefulness. At night, the accumulating sleep pressure reaches its peak (threshold) whereby it overrides the circadian alerting drive and promotes sleep. During the night, sleep is maintained by the residual homeostatic sleep drive coupled with diminution of the circadian alerting signal (Adapted from Edgar et al., 1993).
Figure 4
Figure 4
Sleep homeostasis in sleep-promoting effects of alcohol. A single dose (3 g/kg; intragastric) of alcohol, administered at the onset of the circadian active period, inhibits wake-promoting cholinergic neurons of the BF (Panel A & B) to promote NREM sleep as shown by a significant reduction in sleep onset latency (inset in Panel C) coupled with a significant increase in the amount of time spent in NREM sleep (Panel C). However, blockade of AD A1R in the BF resulted in an attenuation of alcohol- induced sleep promotion (Panel D), whereas local, reverse microdialysis perfusion of pharmacological relevant doses of alcohol into the BF significantly increased extracellular AD in the BF (Panel E; inset describes AD chromatogram) implicating adenosinergic mechanisms in alcohol-induced sleep promotion [adapted from Sharma et al., 2010b and Thakkar et al., 2010]. Lastly, in contrast to sham controls, animals with a selective lesion of the BF cholinergic neurons displayed attenuated alcohol-induced sleep [Panel F; unpublished data]; *= p < 0.05.
Figure 4
Figure 4
Sleep homeostasis in sleep-promoting effects of alcohol. A single dose (3 g/kg; intragastric) of alcohol, administered at the onset of the circadian active period, inhibits wake-promoting cholinergic neurons of the BF (Panel A & B) to promote NREM sleep as shown by a significant reduction in sleep onset latency (inset in Panel C) coupled with a significant increase in the amount of time spent in NREM sleep (Panel C). However, blockade of AD A1R in the BF resulted in an attenuation of alcohol- induced sleep promotion (Panel D), whereas local, reverse microdialysis perfusion of pharmacological relevant doses of alcohol into the BF significantly increased extracellular AD in the BF (Panel E; inset describes AD chromatogram) implicating adenosinergic mechanisms in alcohol-induced sleep promotion [adapted from Sharma et al., 2010b and Thakkar et al., 2010]. Lastly, in contrast to sham controls, animals with a selective lesion of the BF cholinergic neurons displayed attenuated alcohol-induced sleep [Panel F; unpublished data]; *= p < 0.05.
Figure 4
Figure 4
Sleep homeostasis in sleep-promoting effects of alcohol. A single dose (3 g/kg; intragastric) of alcohol, administered at the onset of the circadian active period, inhibits wake-promoting cholinergic neurons of the BF (Panel A & B) to promote NREM sleep as shown by a significant reduction in sleep onset latency (inset in Panel C) coupled with a significant increase in the amount of time spent in NREM sleep (Panel C). However, blockade of AD A1R in the BF resulted in an attenuation of alcohol- induced sleep promotion (Panel D), whereas local, reverse microdialysis perfusion of pharmacological relevant doses of alcohol into the BF significantly increased extracellular AD in the BF (Panel E; inset describes AD chromatogram) implicating adenosinergic mechanisms in alcohol-induced sleep promotion [adapted from Sharma et al., 2010b and Thakkar et al., 2010]. Lastly, in contrast to sham controls, animals with a selective lesion of the BF cholinergic neurons displayed attenuated alcohol-induced sleep [Panel F; unpublished data]; *= p < 0.05.
Figure 4
Figure 4
Sleep homeostasis in sleep-promoting effects of alcohol. A single dose (3 g/kg; intragastric) of alcohol, administered at the onset of the circadian active period, inhibits wake-promoting cholinergic neurons of the BF (Panel A & B) to promote NREM sleep as shown by a significant reduction in sleep onset latency (inset in Panel C) coupled with a significant increase in the amount of time spent in NREM sleep (Panel C). However, blockade of AD A1R in the BF resulted in an attenuation of alcohol- induced sleep promotion (Panel D), whereas local, reverse microdialysis perfusion of pharmacological relevant doses of alcohol into the BF significantly increased extracellular AD in the BF (Panel E; inset describes AD chromatogram) implicating adenosinergic mechanisms in alcohol-induced sleep promotion [adapted from Sharma et al., 2010b and Thakkar et al., 2010]. Lastly, in contrast to sham controls, animals with a selective lesion of the BF cholinergic neurons displayed attenuated alcohol-induced sleep [Panel F; unpublished data]; *= p < 0.05.
Figure 4
Figure 4
Sleep homeostasis in sleep-promoting effects of alcohol. A single dose (3 g/kg; intragastric) of alcohol, administered at the onset of the circadian active period, inhibits wake-promoting cholinergic neurons of the BF (Panel A & B) to promote NREM sleep as shown by a significant reduction in sleep onset latency (inset in Panel C) coupled with a significant increase in the amount of time spent in NREM sleep (Panel C). However, blockade of AD A1R in the BF resulted in an attenuation of alcohol- induced sleep promotion (Panel D), whereas local, reverse microdialysis perfusion of pharmacological relevant doses of alcohol into the BF significantly increased extracellular AD in the BF (Panel E; inset describes AD chromatogram) implicating adenosinergic mechanisms in alcohol-induced sleep promotion [adapted from Sharma et al., 2010b and Thakkar et al., 2010]. Lastly, in contrast to sham controls, animals with a selective lesion of the BF cholinergic neurons displayed attenuated alcohol-induced sleep [Panel F; unpublished data]; *= p < 0.05.
Figure 4
Figure 4
Sleep homeostasis in sleep-promoting effects of alcohol. A single dose (3 g/kg; intragastric) of alcohol, administered at the onset of the circadian active period, inhibits wake-promoting cholinergic neurons of the BF (Panel A & B) to promote NREM sleep as shown by a significant reduction in sleep onset latency (inset in Panel C) coupled with a significant increase in the amount of time spent in NREM sleep (Panel C). However, blockade of AD A1R in the BF resulted in an attenuation of alcohol- induced sleep promotion (Panel D), whereas local, reverse microdialysis perfusion of pharmacological relevant doses of alcohol into the BF significantly increased extracellular AD in the BF (Panel E; inset describes AD chromatogram) implicating adenosinergic mechanisms in alcohol-induced sleep promotion [adapted from Sharma et al., 2010b and Thakkar et al., 2010]. Lastly, in contrast to sham controls, animals with a selective lesion of the BF cholinergic neurons displayed attenuated alcohol-induced sleep [Panel F; unpublished data]; *= p < 0.05.
Figure 5
Figure 5
Impaired sleep homeostasis is the cause of sleep disruptions observed during alcohol withdrawal. A significant increase in wakefulness coupled with a concomitant reduction in sleep (NREM and REM) (Panel A), along with increased activation of wake- promoting BF cholinergic neurons (Panel B) was observed during acute alcohol withdrawal. In addition, there was a significant reduction in the expression of ENT1 and A1R in the BF (Panel C) during alcohol withdrawal, resulting in an absence of a sleep deprivation-induced increase in AD in the BF [Panel D; adapted from Sharma et al., 2010]; *= p < 0.05.
Figure 5
Figure 5
Impaired sleep homeostasis is the cause of sleep disruptions observed during alcohol withdrawal. A significant increase in wakefulness coupled with a concomitant reduction in sleep (NREM and REM) (Panel A), along with increased activation of wake- promoting BF cholinergic neurons (Panel B) was observed during acute alcohol withdrawal. In addition, there was a significant reduction in the expression of ENT1 and A1R in the BF (Panel C) during alcohol withdrawal, resulting in an absence of a sleep deprivation-induced increase in AD in the BF [Panel D; adapted from Sharma et al., 2010]; *= p < 0.05.
Figure 5
Figure 5
Impaired sleep homeostasis is the cause of sleep disruptions observed during alcohol withdrawal. A significant increase in wakefulness coupled with a concomitant reduction in sleep (NREM and REM) (Panel A), along with increased activation of wake- promoting BF cholinergic neurons (Panel B) was observed during acute alcohol withdrawal. In addition, there was a significant reduction in the expression of ENT1 and A1R in the BF (Panel C) during alcohol withdrawal, resulting in an absence of a sleep deprivation-induced increase in AD in the BF [Panel D; adapted from Sharma et al., 2010]; *= p < 0.05.
Figure 5
Figure 5
Impaired sleep homeostasis is the cause of sleep disruptions observed during alcohol withdrawal. A significant increase in wakefulness coupled with a concomitant reduction in sleep (NREM and REM) (Panel A), along with increased activation of wake- promoting BF cholinergic neurons (Panel B) was observed during acute alcohol withdrawal. In addition, there was a significant reduction in the expression of ENT1 and A1R in the BF (Panel C) during alcohol withdrawal, resulting in an absence of a sleep deprivation-induced increase in AD in the BF [Panel D; adapted from Sharma et al., 2010]; *= p < 0.05.
Figure 6
Figure 6
Sleep homeostasis in binge alcohol-induced sleep disruptions. All 4 animals displayed an increase in AD in the BF during 4 h of binge alcohol consumption (Panel A) coupled with a significant increase in NREM sleep during the active period, immediately after the completion of 4 h of binge drinking. However, during the subsequent 12 h of the light (sleep) period, NREM sleep was significantly reduced, especially during the last 9 h of the light period. No change was observed during the first 3 h of the light period, suggesting that Process C, regulating the timing of sleep, remained unaffected (Panel B).
Figure 6
Figure 6
Sleep homeostasis in binge alcohol-induced sleep disruptions. All 4 animals displayed an increase in AD in the BF during 4 h of binge alcohol consumption (Panel A) coupled with a significant increase in NREM sleep during the active period, immediately after the completion of 4 h of binge drinking. However, during the subsequent 12 h of the light (sleep) period, NREM sleep was significantly reduced, especially during the last 9 h of the light period. No change was observed during the first 3 h of the light period, suggesting that Process C, regulating the timing of sleep, remained unaffected (Panel B).
Figure 7
Figure 7
A putative mechanism describing the disruption of sleep homeostasis after alcohol consumption. Since alcohol is a potent somnogen, consumption of alcohol during the evening hours (after 6:00 PM) will promote NREM sleep and disrupt sleep homeostasis (“left shift”), resulting in sleep disruptions manifested by a compensatory reduction in NREM sleep during the second half of the night (see Fig. 3 to compare).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Agapito MA, Barreira JC, Logan RW, Sarkar DK. Evidence for possible period 2 gene mediation of the effects of alcohol exposure during the postnatal period on genes associated with maintaining metabolic signaling in the mouse hypothalamus. Alcoholism: Clinical and Experimental Research. 2013;37:263–269. - PMC - PubMed
    1. Aguayo LG, Peoples RW, Yeh HH, Yevenes GE. GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions? Current Topics in Medicinal Chemistry. 2002;2:869–885. - PubMed
    1. Armitage R, Hoffmann R, Conroy DA, Arnedt JT, Brower KJ. Effects of a 3-hour sleep delay on sleep homeostasis in alcohol dependent adults. Sleep. 2012;35:273–278. - PMC - PubMed
    1. Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep-wake regulation. Progress in Neurobiology. 2004;73:379–396. - PubMed
    1. Batista LC, Prediger RD, Morato GS, Takahashi RN. Blockade of adenosine and dopamine receptors inhibits the development of rapid tolerance to ethanol in mice. Psychopharmacology (Berl) 2005;181:714–721. - PubMed

Publication types

MeSH terms