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Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety

Award Number: K01AA028541
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety - Alcohol use disorder (AUD) affects ~17 million Americans, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $249 billion annually. Humans with AUD often experience negative affect during withdrawal (WD), and depressed mood and anxiety are positively correlated with relapse during abstinence. The neurobiological mechanisms underlying an individual’s response to alcohol, and his/her propensity to develop AUD, are not entirely understood. Acute and chronic alcohol alter neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA), and chronic alcohol also alters neurotransmission in the central amygdala (CeA), an area involved in increased anxiety during WD. There is a functional connection between the VTA and CeA, and although each of these regions is important for addictive behavior, the role of the connection between them in addictive behaviors is unknown. Our preliminary data indicate that alcohol WD activates the VTA-CeA circuit in alcohol-dependent animals. The goal of this K01 proposal is to determine the mechanism underlying this circuit activation, as well as the contribution of the circuit to increased anxiety-like behavior during WD. The overarching hypothesis of this proposal is that CeA-projecting VTA dopamine (DA) neurons become activated during alcohol WD via an orexin 1 receptor (OX1R)-mediated mechanism, and that activation of this circuit is critical in the development of dependence-associated increased anxiety-like behavior during acute WD. To test this hypothesis, the proposal will utilize a combination of anatomical, cellular, imaging, circuit-based and behavioral techniques. This proposal will provide a promising young scientist with vital research training and professional development opportunities facilitated by experiments that use an integrative approach to test the predictions that: (1) increased VTA-CeADA activity observed in vitro during WD from chronic alcohol is mediated by OX1R/endocannabinoid (eCB) signaling, (2) that increased CeA activity observed in vivo during WD from chronic alcohol is mediated by increased DA input from the VTA, and (3) that VTA OX1R/eCB signaling mediates alcohol WD-induced anxiety-like behavior. The results of these studies will open new avenues of neuroscientific investigation exploring the crosstalk between brain reward and brain stress systems in addiction. This work may also inform development of treatment strategies for reducing negative affective symptoms in individuals with AUD, leading to improvements in quality of life and health of affected individuals, and decreasing morbidity associated with these disorders.


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: 2026 ( Subtotal = $163,617 )
2026	2026	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	5	4/17/2026	NON-COMPETING CONTINUATION	$163,617
														Subtotal = $163,617

Issue Date FY: 2025 ( Subtotal = $163,617 )
2025	2025	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	4	4/22/2025	NON-COMPETING CONTINUATION	$163,617
														Subtotal = $163,617

Issue Date FY: 2024 ( Subtotal = $163,617 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	3	2/8/2024	NON-COMPETING CONTINUATION	$163,617
														Subtotal = $163,617

Issue Date FY: 2023 ( Subtotal = $163,617 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	2	2/15/2023	NON-COMPETING CONTINUATION	$163,617
														Subtotal = $163,617

Issue Date FY: 2022 ( Subtotal = $163,617 )
2022	2022	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	1	2/8/2022	NEW	$163,617
														Subtotal = $163,617

Grand Total All Awards = $818,085

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Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety

Award Number: K01AA028541

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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