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Effects of alcohol on sleep/activity rhythms: Focus on Hypocretin/Orexin

Award Number: R01AA006059
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1992
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Effects of alcohol on sleep/activity rhythms: Focus on Hypocretin/Orexin - PROJECT SUMMARY/ABSTRACT Clinical studies have demonstrated that drinking typically begins in adolescence and may lead to alcohol use disorders (AUD). Both younger and older adults with heavy drinking/AUDs are twice as likely to have insomnia that can last for several years. Yet the complex interactions between sleep, drinking, and maintenance of sobriety remain poorly understood despite their profound clinical implications. We postulate that cycles of binge drinking and withdrawal can lead to hyper-arousal states that disrupt sleep and may further drive drinking. One barrier to progress in testing this hypothesis has been the lack of translatable animal models that would allow the control necessary to investigate the long-term effects of alcohol on sleep and daytime functioning. Studies from our laboratory, in rats, have demonstrated that moderate ethanol exposure, either in adolescence or in adulthood, can produce long-term changes in the sleep/wake EEG that mirror the human condition, as well as an enhancement of drinking in adulthood. Alcohol studies in human subjects have recently focused not only on nighttime polysomnographic findings but also on daytime sleepiness and disrupted activity levels, as measured by “fit bit” devices. We propose to further test a “fit bit” system that we have developed in rats to monitor alcohol-induced sleep/wake disturbance, as well as use it to assess the efficacy of potential therapeutic interventions, and to test mechanistic physiological hypotheses related to the etiology of alcohol-induced disturbances of sleep and functional wakefulness. A prominent role of the hypothalamic peptide hypocretin/ orexin (Hct/OX) in homeostatic control of both the sleep/wake cycle and ethanol-seeking and drinking behaviors has been demonstrated. We have also shown partial pharmacological reversal of alcohol-induced sleep pathology by Hct/OX antagonists, however, we do not know if they also impact drinking. New pharmacological studies will test the specificity of the Hct/OX1 vs. Hct/OX2 receptor, vs. dual receptor antagonism, to modify sleep vs. drinking following alcohol. We have also demonstrated that alcohol exposure increases hypothalamic Hct/OX, and RNA-seq/ ATAC-seq studies show that the Hct/OX2 receptor gene is impacted in frontal cortex. The new mechanistic studies we propose will focus on the hypothalamic Hct/OX system using siRNA-mediated hypocretin/ orexin OX1 and OX2 knockdown, gene expression using RNA-seq, and epigenetic changes using ATAC-seq. Such studies could also inform precision/personalized medicine decisions by adding evidenced-based data to the suggestion that Hct/OX1 antagonists could be used for individuals with AUD with enhanced craving and Hct/OX2 antagonists for those with more profound sleep disturbances, and dual receptor antagonists for those with both.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $449,080 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	30	8/13/2025	NON-COMPETING CONTINUATION	$449,080
														Subtotal = $449,080

Issue Date FY: 2024 ( Subtotal = $446,188 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	29	6/18/2024	NON-COMPETING CONTINUATION	$446,188
														Subtotal = $446,188

Issue Date FY: 2023 ( Subtotal = $435,784 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	28	6/21/2023	NON-COMPETING CONTINUATION	$435,784
														Subtotal = $435,784

Issue Date FY: 2022 ( Subtotal = $460,300 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	27	8/15/2022	COMPETING CONTINUATION	$460,300
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	002	27	9/12/2022	COMPETING CONTINUATION	$361
2022	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	26	9/12/2022	NON-COMPETING CONTINUATION	-$361
														Subtotal = $460,300

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	26	5/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $435,375 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	26	5/14/2019	NON-COMPETING CONTINUATION	$435,375
														Subtotal = $435,375

Issue Date FY: 2018 ( Subtotal = $435,375 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	25	5/31/2018	NON-COMPETING CONTINUATION	$435,375
														Subtotal = $435,375

Issue Date FY: 2017 ( Subtotal = $435,375 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	24	5/31/2017	NON-COMPETING CONTINUATION	$435,375
														Subtotal = $435,375

Issue Date FY: 2016 ( Subtotal = $433,125 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	23	5/25/2016	NON-COMPETING CONTINUATION	$433,125
														Subtotal = $433,125

Issue Date FY: 2015 ( Subtotal = $416,306 )
2015	2015	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	22	8/31/2015	COMPETING CONTINUATION	$416,306
														Subtotal = $416,306

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	21	4/10/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $405,733 )
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	21	7/6/2011	NON-COMPETING CONTINUATION	$25,833
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	21	2/28/2011	NON-COMPETING CONTINUATION	$379,900
														Subtotal = $405,733

Issue Date FY: 2010 ( Subtotal = $422,111 )
2010	2010	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	20	3/1/2010	NON-COMPETING CONTINUATION	$422,111
														Subtotal = $422,111

Issue Date FY: 2009 ( Subtotal = $426,375 )
2009	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	19	3/2/2009	NON-COMPETING CONTINUATION	$383,738
2009	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	19	5/5/2009	NON-COMPETING CONTINUATION	$42,637
														Subtotal = $426,375

Issue Date FY: 2008 ( Subtotal = $426,375 )
2008	2008	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	18	2/28/2008	NON-COMPETING CONTINUATION	$426,375
														Subtotal = $426,375

Issue Date FY: 2007 ( Subtotal = $419,400 )
2007	2007	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	17	5/8/2007	COMPETING CONTINUATION	$419,400
														Subtotal = $419,400

Issue Date FY: 2004 ( Subtotal = $370,400 )
2004	2004	SCRIPPS RESEARCH INSTITUTE, TPC 7	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	16	2/25/2004	NON-COMPETING CONTINUATION	$370,400
														Subtotal = $370,400

Issue Date FY: 2003 ( Subtotal = $370,400 )
2003	2003	SCRIPPS RESEARCH INSTITUTE, TPC 7	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	15		NON-COMPETING CONTINUATION	$370,400
														Subtotal = $370,400

Issue Date FY: 2002 ( Subtotal = $324,100 )
2002	2002	SCRIPPS RESEARCH INSTITUTE, TPC 7	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	14	2/28/2002	NON-COMPETING CONTINUATION	$324,100
														Subtotal = $324,100

Issue Date FY: 2001 ( Subtotal = $256,674 )
2001	2001	SCRIPPS RESEARCH INSTITUTE, TPC 7	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	13	3/1/2001	NON-COMPETING CONTINUATION	$256,674
														Subtotal = $256,674

Issue Date FY: 2000 ( Subtotal = $256,674 )
2000	2000	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	12	3/1/2000	COMPETING CONTINUATION	$256,674
														Subtotal = $256,674

Issue Date FY: 1999 ( Subtotal = $26,445 )
1999	1999	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	11	8/24/1999	SUPPLEMENT FOR EXPANSION	$26,445
														Subtotal = $26,445

Grand Total All Awards = $7,651,595

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Effects of alcohol on sleep/activity rhythms: Focus on Hypocretin/Orexin

Award Number: R01AA006059

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/1992

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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