Abstract:
BACKGROUND:Alcohol use disorder (AUD) develops after chronic and heavy use of alcohol. Insomnia, a hallmark of AUD, plays a crucial role in the development of AUD. However, the causal mechanisms are unknown. Since chronic alcohol reduces acetylated histones and disrupts the epigenome, we hypothesized that chronic alcohol exposure will reduce acetylated histones in wake-promoting regions of the brain to cause insomnia during alcohol withdrawal. METHODS:Adult male C57BL/6J mice, surgically instrumented for electrophysiological monitoring of sleep-wakefulness, were exposed to chronic alcohol (6.8%) consumption using Lieber-DeCarli liquid diet. Three experiments were performed. First, the effect of chronic alcohol consumption was examined on sleep-wakefulness during 7 days of withdrawal. Second, the expression of acetylated histones, H3 lysine 14 (AcH3K14), was examined in two major sleep-wake regulatory brain regions: basal forebrain (BF) and lateral hypothalamus (LH) of the brain by using western blotting. Next, blockade of histone deacetylase, via systemic administration of TSA was examined on alcohol-induced changes in sleep-wakefulness. RESULTS:Alcoholic mice displayed a significant reduction in the quality and quantity of NREM sleep coupled with a significant increase in wakefulness that lasted for several days during alcohol withdrawal. In addition, alcoholic mice displayed a significant reduction in the expression of AcH3K14 in both BF and LH. Systemic administration of TSA significantly attenuated insomnia and improved the quality and quantity of sleep during alcohol withdrawal. CONCLUSIONS:Based on our results, we suggest that a causal relationship exists between reduced histone acetylation and insomnia during alcohol withdrawal.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Sharma R,Sahota P,Thakkar MMdoi
10.1016/j.neuropharm.2020.108332subject
Has Abstractpub_date
2020-12-01 00:00:00pages
108332eissn
0028-3908issn
1873-7064pii
S0028-3908(20)30400-7journal_volume
180pub_type
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更新日期:2005-01-01 00:00:00
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