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Alcohol/Stress Effects on Kappa Opioid Receptors in the Amygdala and Accumbens

Award Number: U01AA014091
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Stress is a well-known factor in promoting heavy drinking and relapse to drinking in individuals with alcohol use disorder (AUD), and avoidance of the negative affective symptoms of ethanol withdrawal (e.g. anxiety and depression) is also believed to play a critical role in relapse. Further, disorders of negative affect may predispose individuals to AUD and the interaction of these disorders may exacerbate symptoms of both. One component of the brain stress system is comprised of the neuropeptide dynorphin and its target, the kappa opioid receptors (KOR), and it is augmented following exposure to chronic alcohol and/or stress. We will use a mouse model of chronic intermittent ethanol (CIE) exposure combined with either chronic forced swim stress or mouse single prolonged stress to understand the role that KORs play in the maladaptive neurobiological changes induced by stress/ethanol interactions. Our previous work revealed that the function of the dynorphin/KOR system in the nucleus accumbens (NAc) was robustly up-regulated by chronic ethanol exposure and withdrawal in a time/exposure dependent manner in both the CIE model in mice and in a long- term voluntary ethanol drinking model in monkeys. In addition, in mice we found that systemic administration of a KOR antagonist reduced anxiety/compulsive behaviors (marble burying) and withdrawal-induced excessive drinking. Dopamine (DA) is involved in negative affective responses to stress, and DA terminals are known targets of KOR activity. Therefore, we will use a multipronged approach to examine KOR regulation of DA signaling in the NAc, which regulates motivation to drink alcohol, and the basolateral amygdala (BLA), which regulates stress/anxiety-related behaviors, using conditional viral knockdown of KORs from these regions, microdialysis to assess basal dopamine and dynorphin levels following exposure to CIE and/or stress paradigms, and the fluorescent sensor dLight to query real-time dopamine signaling in these animals in response to time-locked behaviors. The overall goal of this proposal is to define the role of KORs on DA signaling in the NAc and BLA following exposure to chronic alcohol and/or stress, and how these adaptations in stress-responsive limbic circuitry nodes that are responsible for withdrawal-associated negative affect can be targeted for the treatment of AUD.


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: 2024 ( Subtotal = $418,501 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	22	1/18/2024	NON-COMPETING CONTINUATION	$418,501
														Subtotal = $418,501

Issue Date FY: 2023 ( Subtotal = $465,000 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	21	1/31/2023	NON-COMPETING CONTINUATION	$465,000
2023	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	002	20	5/17/2023	COMPETING CONTINUATION	-$27,137
2023	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	19	5/17/2023	NON-COMPETING CONTINUATION	$27,137
														Subtotal = $465,000

Issue Date FY: 2022 ( Subtotal = $465,000 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	005	20	8/24/2022	COMPETING CONTINUATION	$0
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	004	20	7/20/2022	COMPETING CONTINUATION	$177,697
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	20	2/16/2022	COMPETING CONTINUATION	$465,000
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	002	20	3/22/2022	COMPETING CONTINUATION	$0
2022	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	003	19	7/20/2022	NON-COMPETING CONTINUATION	-$177,697
2022	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	19	2/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $465,000

Issue Date FY: 2021 ( Subtotal = $348,750 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	19	2/15/2021	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2020 ( Subtotal = $348,750 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	18	1/28/2020	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2019 ( Subtotal = $348,750 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	17	2/20/2019	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2018 ( Subtotal = $348,750 )
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	16	5/23/2018	NON-COMPETING CONTINUATION	$34,875
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	16	1/17/2018	NON-COMPETING CONTINUATION	$313,875
														Subtotal = $348,750

Issue Date FY: 2017 ( Subtotal = $348,750 )
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	002	15	5/12/2017	COMPETING CONTINUATION	$19,358
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	15	2/1/2017	COMPETING CONTINUATION	$348,750
2017	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	14	5/12/2017	EXTENSION WITH OR WITHOUT FUNDS	-$19,358
														Subtotal = $348,750

Issue Date FY: 2016 ( Subtotal = $258,374 )
2016	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	14	1/26/2016	EXTENSION WITH OR WITHOUT FUNDS	$258,374
														Subtotal = $258,374

Issue Date FY: 2015 ( Subtotal = $250,623 )
2015	2015	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	13	1/12/2015	NON-COMPETING CONTINUATION	$250,623
														Subtotal = $250,623

Issue Date FY: 2014 ( Subtotal = $250,623 )
2014	2014	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	12	3/5/2014	NON-COMPETING CONTINUATION	$18,085
2014	2014	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	12	1/10/2014	NON-COMPETING CONTINUATION	$232,538
														Subtotal = $250,623

Issue Date FY: 2013 ( Subtotal = $240,288 )
2013	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	11	7/15/2013	NON-COMPETING CONTINUATION	$7,750
2013	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	11	1/21/2013	NON-COMPETING CONTINUATION	$232,538
														Subtotal = $240,288

Issue Date FY: 2012 ( Subtotal = $258,374 )
2012	2012	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	10	2/9/2012	COMPETING CONTINUATION	$258,374
														Subtotal = $258,374

Issue Date FY: 2011 ( Subtotal = $267,661 )
2011	2011	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	9	1/25/2011	NON-COMPETING CONTINUATION	$250,629
2011	2011	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	9	7/1/2011	NON-COMPETING CONTINUATION	$17,032
														Subtotal = $267,661

Issue Date FY: 2010 ( Subtotal = $270,366 )
2010	2010	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	8	1/27/2010	NON-COMPETING CONTINUATION	$270,366
2010	2009	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Trans-NIH Recovery Act Research Support	001	7	9/3/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $270,366

Issue Date FY: 2009 ( Subtotal = $522,482 )
2009	2009	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	7	1/30/2009	NON-COMPETING CONTINUATION	$238,626
2009	2009	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Trans-NIH Recovery Act Research Support	002	7	9/21/2009	SUPPLEMENT FOR EXPANSION	$257,340
2009	2009	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	7	5/7/2009	NON-COMPETING CONTINUATION	$26,516
														Subtotal = $522,482

Issue Date FY: 2008 ( Subtotal = $273,403 )
2008	2008	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	6	1/31/2008	NON-COMPETING CONTINUATION	$273,403
														Subtotal = $273,403

Grand Total All Awards = $6,540,261

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Alcohol/Stress Effects on Kappa Opioid Receptors in the Amygdala and Accumbens

Award Number: U01AA014091

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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