Considerable evidence exists to suggest that ethanol consumption has significant impact on nocturnal sleep and daytime alertness in humans. While low to moderate intake of ethanol in non-alcoholics improves sleep, high doses of ethanol intake produces severe sleep disruptions. Alcoholics, both during drinking period as well as during withdrawal suffer from a multitude of sleep disturbances including difficulty in initiating and maintaining sleep during the night. The broad objective of this program of research is to understand the cellular and molecular mechanisms mediating the somnogenic effects of ethanol and thereby provide a sound basis to the understanding and treatment of ethanol related sleep disorder. The key techniques to be used are novel combinations of multi-disciplinary methods including the: A) in vivo """"""""on-line"""""""" microdialysis sampling coupled with HPLC measurement of adenosine and electrographic monitoring of sleep-wakefulness following ethanol administration. B) In vivo """"""""off line"""""""" c-Fos immunohistochemistry to determine the neuronal phenotypes mediating the somnogenic effects of ETOH. Our broad hypothesis is that adenosine via A1 receptor is responsible for mediating the somnogenic effects of ethanol. We predict that acute ethanol administration will increase extracellular levels of adenosine in the cholinergic basal forebrain. Increased adenosine, acting via adenosine A1 receptor, will inhibit the wake-promoting cholinergic neurons of the basal forebrain as evidenced by a reduction in number of cholinergic neurons with c-Fos immunoreactivity. Furthermore, blockade of adenosine transmission by local infusion of adenosine A1 receptors antagonist into the basal forebrain will attenuate the somnogenic effects of ethanol. .

Public Health Relevance

The broad objective of this research program is to understand the cellular and molecular mechanisms responsible for the somnogenic effects of ethanol and thereby to provide a sound basis for the understanding and treatment of sleep disorder associated with ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA017472-01A2
Application #
7738695
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Grandison, Lindsey
Project Start
2009-09-15
Project End
2011-08-31
Budget Start
2009-09-15
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$157,221
Indirect Cost
Name
University of Missouri-Columbia
Department
Neurology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52
Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep (2015) Alcohol disrupts sleep homeostasis. Alcohol 49:299-310
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
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; 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
Nam, Hyung W; McIver, Sally R; Hinton, David J et al. (2012) Adenosine and glutamate signaling in neuron-glial interactions: implications in alcoholism and sleep disorders. Alcohol Clin Exp Res 36:1117-25
Thakkar, Mahesh M (2011) Histamine in the regulation of wakefulness. Sleep Med Rev 15:65-74
Thakkar, M M; Engemann, S C; Sharma, R et al. (2010) Sleep-wakefulness in alcohol preferring and non-preferring rats following binge alcohol administration. Neuroscience 170:22-7
Sharma, Rishi; Engemann, Samuel C; Sahota, Pradeep et al. (2010) Effects of ethanol on extracellular levels of adenosine in the basal forebrain: an in vivo microdialysis study in freely behaving rats. Alcohol Clin Exp Res 34:813-8
Sharma, Rishi; Engemann, Samuel; Sahota, Pradeep et al. (2010) Role of adenosine and wake-promoting basal forebrain in insomnia and associated sleep disruptions caused by ethanol dependence. J Neurochem 115:782-94

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