SPECIFIC AIMS This proposal continues our investigation of ethanol effects on the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). Alcohol use, abuse and withdrawal have profound effects on sleep and circadian rhythms. Alcohol effects on these two processes likely are closely intertwined since disruptions in circadian functioning are major causes of many sleep irregularities. The long-term goal of our research is to better understand the neural processes contributing to the etiology of these sleep problems, specifically focusing on the role circadian rhythmsOur collaborative research shows that ethanol inhibits photic phase resetting of the SCN circadian clock in vivo and in vitro. The objective of this RO1 proposal is to identify the cellular mechanisms underlying the acute effects of ethanol, and to expand our research to investigate the effects of chronic alcohol and alcohol withdrawal. The major advantage of our collaboration is our ability to interweave complementary in vivo and in vitro experiments that take advantage of the unique aspects of each approach. Our central hypothesis is that ethanol inhibits glutamate signaling in core SCN neurons, which over time leads to up-regulated glutamatergic activity. Our rationale for the proposed studies is that identifying the cellular mechanisms through which ethanol modulates the circadian clock will lead to new insights on treatments that may prevent or overcome this debilitating disease. Therefore, we proposed to pursue the following specific aims:
Specific Aim 1. Determine time-dependent changes in ethanol effects on photic/ glutamate signaling in the SCN: acute vs. tolerance vs. chronic vs. withdrawal. These experiments will characterize the effects of ethanol on the SCN circadian clock through monitoring behavioral and electrophysiological (in vivo and in vitro) rhythms, and how these effects vary depending on the duration of ethanol exposure.
Specific Aim 2. Determine the cellular mechanisms of ethanol actions in the SCN. These experiments will assess the effects of ethanol on in vivo SCN neuropeptide release patterns, and investigate the cellular mechanisms through which ethanol inhibits glutamate-induced phase resetting in vitro.
Specific Aim 3. Determine how ethanol affects non-photic phase resetting. These experiments will assess the effects of acute and chronic ethanol, and ethanol withdrawal, on serotonergic, GABAergic, and NPYergic phase resetting in vivo and in vitro, and probe the mechanisms and locations through which these effects occur.

Public Health Relevance

Alcohol abuse and withdrawal have profound effects on circadian rhythms and sleep. These two phenomena are likely interrelated, since disruptions in circadian functioning are a major cause of many sleep irregularities. Since sleep problemshave been linked to both the development of alcoholism and the likelihood of a relapse in recovering alcoholics, it is important to better understand the neural processes that contribute to the etiology of these sleep problems. The goal of our research is to delineate the effects of acute and chronic ethanol and ethanol withdrawal on circadian rhythms, determine whether these effects are due to direct actions on the circadian clock, and investigate the cellular mechanisms underlying these effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017898-04
Application #
8436332
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Bechtholt-Gompf, Anita
Project Start
2010-03-05
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$302,756
Indirect Cost
$41,777
Name
University of Tennessee Knoxville
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Prosser, Rebecca A; Glass, J David (2015) Assessing ethanol's actions in the suprachiasmatic circadian clock using in vivo and in vitro approaches. Alcohol 49:321-39
Brager, Allison; Prosser, Rebecca A; Glass, J David (2011) Acamprosate-responsive brain sites for suppression of ethanol intake and preference. Am J Physiol Regul Integr Comp Physiol 301:R1032-43
Brager, Allison J; Ruby, Christina L; Prosser, Rebecca A et al. (2011) Acute ethanol disrupts photic and serotonergic circadian clock phase-resetting in the mouse. Alcohol Clin Exp Res 35:1467-74
Brager, Allison J; Prosser, Rebecca A; Glass, J David (2011) Circadian and acamprosate modulation of elevated ethanol drinking in mPer2 clock gene mutant mice. Chronobiol Int 28:664-72
Hammer, Steven B; Ruby, Christina L; Brager, Allison J et al. (2010) Environmental modulation of alcohol intake in hamsters: effects of wheel running and constant light exposure. Alcohol Clin Exp Res 34:1651-8
Prosser, Rebecca A; Glass, J David (2009) The mammalian circadian clock exhibits acute tolerance to ethanol. Alcohol Clin Exp Res 33:2088-93
Ruby, Christina L; Prosser, Rebecca A; DePaul, Marc A et al. (2009) Acute ethanol impairs photic and nonphotic circadian phase resetting in the Syrian hamster. Am J Physiol Regul Integr Comp Physiol 296:R411-8
Ruby, Christina L; Brager, Allison J; DePaul, Marc A et al. (2009) Chronic ethanol attenuates circadian photic phase resetting and alters nocturnal activity patterns in the hamster. Am J Physiol Regul Integr Comp Physiol 297:R729-37
McElroy, B; Zakaria, A; Glass, J D et al. (2009) Ethanol modulates mammalian circadian clock phase resetting through extrasynaptic GABA receptor activation. Neuroscience 164:842-8