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The role of corticotropin releasing factor in binge-like ethanol drinking

Award Number: R01AA022048
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: 07/15/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The role of corticotropin releasing factor in binge-like ethanol drinking - Project Summary Alcohol (ethanol) dependence and relapse in abstinent alcoholics are major health problems throughout the world and neurochemical pathways that modulate these disorders are currently under investigation. However, the neurobiology underlying binge drinking, a dangerous pattern of behavior that proceeds and contributes to dependence, has received far less attention. Thus, it is of paramount importance to identify the neurocircuitry in the brain that modulates binge drinking as such knowledge will provide insight into the initial stages of alcohol use disorders (AUDs) and will shed new light on avenues for treating early-stage AUDs prior to the development of dependence. During the last funding period of this grant, our laboratory has provided converging evidence that corticotropin releasing factor (CRF) receptor signaling, via neurocircuitry providing cross-talk between brain regions that integrate emotions/stress responses with those that motivate reward-seeking behaviors, modulates binge-like ethanol drinking in mice. Furthermore, preliminary data described in this grant provide converging evidence that of a novel circuit linking stress and reward systems modulates binge-like ethanol intake in a sex- dependent manner, a highly significant discovery given our very limited understanding of the mechanisms that drive sex differences in ethanol intake and AUDs. A critical player in integrating reward-directed behaviors is the lateral hypothalamus (LH), and we provide preliminary evidence that blocking CRF type-1 receptors (CRF1R) in the LH, as well as chemogenetic silencing of a CRF+ pathway from the central amygdala (CeA) to the LH, reduce binge-like ethanol intake in male, but not female mice. The guiding hypothesis for the current grant is that CRF receptor signaling in the LH modulates binge-like ethanol drinking, which involves the CRF+ CeA → LH pathway, and that a history of binge-like ethanol drinking will promote plasticity within this CRF circuit linking stress and reward systems, all in a sex-dependent manner. We will use powerful and innovative chemogenetic, transgenic, electrophysiological, and histological approaches to test the hypothesis that LH-infusion of CRF1R antagonist and CRF type-2 receptor (CRF2R) agonist, and knockdown of CRF1R in the LH, will protect against binge-like ethanol drinking (Aim 1), chemogenetic inactivation or activation of CRF+ CeA neurons that project to the LH will blunt or increase binge-like ethanol intake, respectively (Aim 2), and a history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and signaling in the CeA → LH neurocircuitry. Because our preliminary data provided converging evidence that CRF signaling in this pathway modulates binge-like ethanol drinking primarily in male mice, each aim is sufficiently powered to characterize sex differences. The aims of this grant will address a critical gap in the literature on the role of CRF in bridging functional communication between brain regions integrating stress/emotion with those the modulate reward- seeking, provide novel insight into mechanisms that guide sex differences in binge-like ethanol intake, and will shed new light on avenues for treating early-stage AUDs prior to the development of dependence.


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 = $349,875 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	9	5/8/2025	NON-COMPETING CONTINUATION	$349,875
														Subtotal = $349,875

Issue Date FY: 2024 ( Subtotal = $349,875 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	8	3/22/2024	NON-COMPETING CONTINUATION	$314,888
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	8	5/10/2024	NON-COMPETING CONTINUATION	$34,987
														Subtotal = $349,875

Issue Date FY: 2023 ( Subtotal = $349,875 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	7	3/18/2023	NON-COMPETING CONTINUATION	$349,875
														Subtotal = $349,875

Issue Date FY: 2022 ( Subtotal = $349,875 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	6	4/1/2022	COMPETING CONTINUATION	$349,875
														Subtotal = $349,875

Issue Date FY: 2020 ( Subtotal = -$714 )
2020	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	5	11/23/2019	NON-COMPETING CONTINUATION	-$714
														Subtotal = -$714

Issue Date FY: 2017 ( Subtotal = $223,165 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	5	5/31/2017	NON-COMPETING CONTINUATION	$296,000
2017	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	4	4/10/2017	SUPPLEMENT FOR EXPANSION	-$72,835
														Subtotal = $223,165

Issue Date FY: 2016 ( Subtotal = $368,835 )
2016	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	4	8/24/2016	SUPPLEMENT FOR EXPANSION	$72,835
2016	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	4	5/17/2016	EXTENSION WITH OR WITHOUT FUNDS	$296,000
														Subtotal = $368,835

Issue Date FY: 2015 ( Subtotal = $287,120 )
2015	2015	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	3	4/30/2015	NON-COMPETING CONTINUATION	$287,120
														Subtotal = $287,120

Issue Date FY: 2014 ( Subtotal = $287,120 )
2014	2014	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	2	5/21/2014	NON-COMPETING CONTINUATION	$287,120
														Subtotal = $287,120

Issue Date FY: 2013 ( Subtotal = $296,000 )
2013	2013	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	1	7/12/2013	NEW	$296,000
														Subtotal = $296,000

Grand Total All Awards = $2,861,026

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The role of corticotropin releasing factor in binge-like ethanol drinking

Award Number: R01AA022048

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: 07/15/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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