The Journal of Neuroscience, June 4, 2014 • 34(23):7733–7734 • 7733

Journal Club

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Adenosine Sheds Light on the Relationship between Alcohol and Sleep

Corinde E. Wiers Department of Psychiatry and Psychotherapy, Charite´—Universita¨tsmedizin Berlin, 10117 Berlin, Germany, and Berlin School of Mind and Brain, Humboldt-Universita¨t zu Berlin, 10099 Berlin, Germany Review of Clasadonte et al.

It has been extensively demonstrated that transporter type 1 (ENT1), leading to in- mice were not forced to run and hence there is a strong association between sleep creased extracellular concentrations of could sleep normally. During the first day and alcohol consumption. While drinking adenosine. In contrast, chronic exposure of sleep restriction, both hippocampal small amounts of alcohol can help one to alcohol downregulates the expression adenosine tone (i.e., adenosine-dependent falling asleep, chronic alcohol use often of ENT1, so that alcohol-mediated inhibi- inhibition of synaptic activity, measured by leads to reductions in the quality of sleep, tion of ENT1 is reduced and extracellular recording field EPSPs in hippocampal and ϳ50% of alcohol-dependent patients adenosine decreases (Nagy et al., 1990). slices that were perfused with an A1 antag- suffer from insomnia (Nam et al., 2012). Furthermore, in vivo rodent studies have onist) and slow-wave activity (a measure However, the causal relationship between shown that adenosine is a key player in the of sleep quality, measured with EEG) in- disturbed sleep and alcohol abuse and de- behavioral effects of alcohol, such as the creased. However, after3dofsleep re- pendence is unclear. Wong et al. (2010) promotion of sleep and the impairment of striction, Clasadonte et al. (2014) found found that sleep problems in children motor movements. For example, as a re- the opposite: both these measures de- were a strong marker of alcohol abuse cent study by Sharma et al. (2014) demon- creased. Reductions in adenosine tone later in life. Moreover, sleep distur- strates, the sleep-promoting effects of lasted for 2 weeks and were likely due to a bances have been shown to be a acute alcohol result from an adenosine A1 loss of source of extracellular adenosine predictor of relapse in recovering receptor-mediated inhibition of orexin rather than an increase in adenosine re- alcohol-dependent patients, presumably neurons in the hypothalamus. These neu- uptake. That is, pharmacologically block- since patients with sleep concerns are rons are known to maintain wakefulness ing ENT1 (which would inhibit adenosine more likely to use alcohol to help them fall when activated, whereas a loss of orexin reuptake) had no effect in sleep-restricted asleep (Nam et al., 2012). neurotransmission in the hypothalamus mice, suggesting that the active delivery of The neurobiological mechanisms un- promotes sleep and can cause narcolepsy extracellular adenosine was affected. derlying the relationship between alcohol (Gerashchenko et al., 2001; Sharma et al., These findings indicate that chronic sleep and sleep remain largely unexplored, but 2014). Moreover, there is increasing evi- restriction impairs sleep homeostasis and adenosine signaling may contribute. Al- dence that the motor-impairing effects of decreases adenosine tone. tered signaling of adenosine in the brain is alcohol are mediated by A1 receptors in Next, the authors investigated the be- involved in the pathophysiology of both several brain areas, including the cerebel- havioral consequences of chronic sleep alcohol dependence and sleep disorders lum, striatum, and cortex (Choi et al., restriction on alcohol sensitivity. Sleep- (Nam et al., 2012). In cell cultures, acute 2004; Nam et al., 2012). Despite these restricted and non-restricted mice were exposure to alcohol inhibits adenosine re- findings, however, whether chronic sleep placed on a rotarod, a rotating cylinder, uptake via the equilibrative nucleoside restriction alters adenosine signaling, and 1 d after chronic sleep restriction. There whether this influences the sensitivity to were no group differences in performance Received March 29, 2014; revised April 25, 2014; accepted April 30, 2014. alcohol, has remained unexplored. on the rotarod when the mice were in a I thank Andrey Verendeev and Scott Stensland for proofreading. Clasadonte and colleagues (2014) have drug-free state. However, after intoxicat- Correspondence should be addressed to Corinde E. Wiers, Berlin School recentlyaddressedthesequestions.C57BL/ ing the animals with alcohol, sleep- of Mind and Brain, Humboldt-Universita¨t zu Berlin, Unter den Linden 6, 10099 Berlin, Germany. E-mail: [email protected]. 6J mice were forced to move on a tread- restricted mice performed better than DOI:10.1523/JNEUROSCI.1274-14.2014 mill for 4 h every6hfor3dinarow, to control mice in that they showed lower Copyright © 2014 the authors 0270-6474/14/347733-02$15.00/0 chronically restrict their sleep. Control latencies to fall and a faster recovery (50% 7734 • J. Neurosci., June 4, 2014 • 34(23):7733–7734 Wiers • Journal Club of the drug-free baseline performance). may lead to more positive experiences of effects of sleep-restriction on alcohol sen- The same effects were found 2 and 4 weeks alcohol, making it more likely to drink sitivity take place. after sleep restriction and were not due larger amounts. Moreover, higher levels Based on the results of Clasadonte et al. to differences in alcohol metabolism. of intake could lead to alcohol tolerance, (2014), a noninvasive strategy to reduce Therefore, the findings demonstrate in which higher doses of alcohol are alcohol sensitivity may be the promotion that chronic sleep-restricted mice were needed to get similar effects, which fur- of sleep. Although more insight is needed less sensitive to the motor-impairing ef- ther increases the risk of abusing alcohol into whether sleep restriction also de- fects of alcohol, an effect that lasted at least or developing dependence (Schuckit, creases motor sway after alcohol intoxica- a month after restriction. Interestingly, 1994). tion in humans, the study of Clasadonte et infusion of an A1 receptor antagonist into The findings of Clasadonte et al. al. (2014) is the beginning of exciting the brain resulted in better rotarod per- (2014) may have clinical importance. Spe- findings regarding the relationship be- formances under the influence of alcohol, cifically, if a reduced motor-impairing tween sleep and alcohol sensitivity and but in control mice only. Although indi- sensitivity to alcohol is a strong predictor consumption. rectly, this suggests that sleep restriction of alcohol consumption (Schuckit, 1994; affects the sensitivity to the motor- Choi et al., 2004) and this sensitivity is impairing effects of alcohol via alterna- related to reduced adenosine levels, then References tions in adenosine signaling. drugs that increase adenosine A1 receptor Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, Diamond I, Bonci A, The findings of Clasadonte et al. signaling could potentially be potent in Messing RO (2004) The type 1 equilibrative (2014) are significant in that they provide reducing alcohol consumption. However, nucleoside transporter regulates ethanol in- evidence for a relationship between sleep both A1 receptor agonists and adenosine toxication and preference. Nat Neurosci restriction and alcohol sensitivity, medi- kinase inhibitors have negative side ef- 7:855–861. CrossRef Medline ated by adenosine signaling. How then is fects, making the process of drug develop- Clasadonte J, McIver SR, Schmitt LI, Halassa MM, decreased sensitivity to alcohol related to ment difficult (Nam et al., 2012). Haydon PG (2014) Chronic sleep restriction alcohol consumption? Although Clasa- Additionally, where in the brain such an disrupts sleep homeostasis and behavioral sensitivity to alcohol by reducing the extracel- donte et al. (2014) did not investigate this intervention could decrease alcohol sensi- lular accumulation of adenosine. J Neurosci directly, evidence from previous mouse tivity and alcohol consumption remains 34:1879–1891. CrossRef Medline and human studies suggests that de- unknown. Clasadonte et al. (2014) re- Diao L, Dunwiddie TV (1996) Interactions be- creased sensitivity of motor behaviors to searched adenosine signaling in the hip- tween ethanol, edogenous adenosine and the impairing effects of alcohol leads to pocampus of sleep-restricted mice, but it adenosine uptake in hippocampal brain slices. increases in alcohol consumption. First, remains unclear whether the effects on al- J Pharmacol Exp Ther 278:542–546. Medline Choi et al. (2004) showed that genetically cohol sensitivity were mediated at the hip- Gerashchenko D, Kohls MD, Greco M, Waleh NS, Salin-Pascual R, Kilduff TS, Lappi DA, Shiro- modified mice missing ENT1 (ENT1-null pocampal level. In fact, it seems unlikely mani PJ (2001) Hypocretin-2-saporin le- mice) were not only less sensitive to the that the hippocampus is related to the sions of the lateral hypothalamus produce acute effects of alcohol on rotarod perfor- motor-impairing effects of alcohol for narcoleptic-like sleep behavior in the rat. mances, but also drank more alcohol than two reasons. First, diminished sensitivity J Neurosci 21:7273–7283. Medline wild-type mice. Since ENT1-null mice to the motor-impairing effects of alcohol Nagy LE, Diamond I, Casso DJ, Franklin C, Gor- had reduced levels of adenosine and A1 and alcohol-intake have been associated don AS (1990) Ethanol increases extracellu- lar adenosine by inhibiting adenosine uptake receptors in the striatum, and the admin- with decreases in adenosine receptors in via the nucleoside transporter. J Biol Chem istration of an A1 agonist decreased the cerebellum, striatum, and cortex 265:1946–1951. Medline drinking in mice, adenosine signaling may (Choi et al., 2004; Nam et al., 2012), but Nam HW, McIver SR, Hinton DJ, Thakkar MM, be directly involved in alcohol sensitivity not in the hippocampus. Second, neither Sari Y, Parkinson FE, Haydon PG, Choi DS and alcohol consumption. Second, hu- alcohol nor an inhibitor of ENT1 in the rat (2012) Adenosine and glutamate signaling in man studies measuring ataxia on the body hippocampus lead to increases in extra- neuron–glial interactions: implications in al- sway test, in which participants wear a cellular adenosine levels (Diao and Dun- coholism and sleep disorders. Alcohol Clin Exp Res 36:1117–1125. CrossRef Medline harness that measures body movements, widdie, 1996). This lack of response hence Schuckit MA (1994) Low level of response to al- showed that lower intensity of both suggests that the sensitivity to alcohol is cohol as a predictor of future alcoholism. Am J alcohol-induced body sway and subjective influenced by adenosine signaling in a dif- Psychiatry 151:184–189. Medline responses to intoxication at age 20 were ferent brain area than the hippocampus. Sharma R, Sahota P, Thakkar MM (2014) Role potent predictors of alcohol abuse or de- Consistent with this, the A1 receptor an- of adenosine and the orexinergic perifornical pendence almost 10 years later (Schuckit, tagonist that decreased sensitivity to alco- hypothalamus in sleep-promoting effects of 1994). This relationship was found for hol in control mice in Clasadonte et al. ethanol. Sleep 37:525–533. CrossRef Medline Wong MM, Brower KJ, Nigg JT, Zucker RA both sons of alcoholics and controls with- (2014) was distributed globally in the (2010) Childhood sleep problems, response out a family history of alcohol depen- brain and may have acted in different inhibition, and alcohol and drug outcomes in dence. Therefore, reduced sensitivity to brain regions. Further studies are neces- adolescence and young adulthood. Alcohol the motor-impairing effects of alcohol sary to investigate where in the brain the Clin Exp Res 34:1033–1044. CrossRef Medline