Intake of alcoholic beverages has significant impact on sleep. Acute alcohol intake in non- alcoholics promotes sleepiness. In contrast, alcoholics, both during drinking period as well as during withdrawal suffer from profound and protracted insomnia and associated sleep disruptions that persist for several months during abstinence. Insomnia and associated sleep disturbances in recovering alcoholics are major risk factors for relapse to alcoholism. Thus, it is imperative that we understand and treat sleep disturbances in recovering alcoholics. The broad objective of this program of research is to elucidate the molecular mechanisms mediating the effects of ethanol on sleep-wakefulness and thereby provide a sound basis for the understanding and treatment of ethanol associated sleep disturbances and alcoholism. Our hypothesis: Profound insomnia and associated sleep disruptions observed during alcohol withdrawal are the result of epigenetic changes in the wake-promoting basal forebrain region. We predict that the expression of transcription factor, FosB/delta FosB will be increased in the wake-promoting basal forebrain region during ethanol withdrawal. We further predict that the expression of Clock protein, a key sleep and circadian regulator with histone acetyltransferase activity, will be reduced in the basal forebrain during ethanol withdrawal. Furthermore, we predict that chronic ethanol exposure will decrease acetylation of histones, H3 and H4, in the basal forebrain. Local and bilateral administration of histone deacetylase inhibitor, trichostatin-A, in the basal forebrain will attenuate chronic ethanol induced insomnia and associated sleep disruptions.

Public Health Relevance

The broad objective of this research program is to understand the molecular mechanisms responsible for causing sleep disruptions during alcohol withdrawal and thereby provide a sound basis for the understanding and treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA020334-02
Application #
8252179
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Noronha, Antonio
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$149,625
Indirect Cost
$30,875
Name
University of Missouri-Columbia
Department
Neurology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep (2015) Alcohol disrupts sleep homeostasis. Alcohol 49:299-310
Sharma, Rishi; Dumontier, Samuel; DeRoode, David et al. (2014) Nicotine infusion in the wake-promoting basal forebrain enhances alcohol-induced activation of nucleus accumbens. Alcohol Clin Exp Res 38:2590-6
Sharma, Rishi; Bradshaw, Kevin; Sahota, Pradeep et al. (2014) Acute binge alcohol administration reverses sleep-wake cycle in Sprague Dawley rats. Alcohol Clin Exp Res 38:1941-6
Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M (2014) Rapid tolerance development to the NREM sleep promoting effect of alcohol. Sleep 37:821-4
Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M (2014) Role of adenosine and the orexinergic perifornical hypothalamus in sleep-promoting effects of ethanol. Sleep 37:525-33
Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M (2014) Nicotine administration in the cholinergic basal forebrain increases alcohol consumption in C57BL/6J mice. Alcohol Clin Exp Res 38:1315-20