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Role of GluN2A and MMPs in the CeA in Dependence-Induced Escalation of Etoh Drinking

Award Number: R21AA030159
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: 08/02/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Role of GluN2A and MMPs in the CeA in Dependence-Induced Escalation of Etoh Drinking - Project Summary The legal status and widespread use of alcohol among the US population is associated with adverse health outcomes in both adolescents and adults. Nearly 88% of the US population have used alcohol at least once during their lifetime and rates of binge drinking and heavy alcohol use continue to be of concern. Pharmacological treatments for alcohol abuse show limited effectiveness and only three medications are FDA approved for treating alcohol dependence. One factor that underlies this problem is a lack of understanding of the mechanisms that contribute to excessive drinking. Recent results from our previous studies show that knock-in mice expressing ethanol resistant GluN2A N-methyl-D-aspartate receptors (NMDARs) drink the same as wild-type mice under baseline conditions but, unlike their wild-type counterparts, fail to escalate their drinking following repeated cycles of chronic intermittent ethanol exposure. These findings suggest that GluN2A NMDARs play a key role for in the loss of control over drinking observed in alcohol dependent subjects. Importantly, a similar lack of escalated drinking is observed following administration of inhibitors of zinc-dependent matrix metalloproteinases (MMPs) either i.c.v. or directly into the central nucleus of the amygdala (CeA). MMPs are key mediators of NMDA-mediated forms of synaptic plasticity where they remodel the extracellular matrix to support new growth and enlargement of glutamatergic dendritic spines. In this proposal we test the overarching hypothesis that MMPs and ethanol-sensitive GluN2A NMDARs in the CeA are critically involved in the transition to heavy drinking that is a hallmark of alcohol dependence. In Aim 1, we use slice electrophysiology, in vivo zymography and western blot analysis to test the hypothesis that CIE-induced changes in CeA neural signaling and MMP activity are absent in the GluN2A knock-in mice. In Aim 2, we use Crispr expressing AAVs and guide RNAs targeting the GluN2A gene to test the hypothesis that the CIE-induced increases in drinking and MMP activity requires functional GluN2A NMDARs in the CeA. The findings from these novel studies will provide critical data to support a future R01 grant application focused on determining which CeA cell types drive the altered drinking phenotype of the GluN2A knock-in mice and whether their expression in other key addiction-related brain areas contribute to this effect.


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 = $0 )
2026	2023	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Alcohol Research Programs	000	2	12/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $179,313 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Alcohol Research Programs	000	2	8/3/2023	NON-COMPETING CONTINUATION	$179,313
														Subtotal = $179,313

Issue Date FY: 2022 ( Subtotal = $217,063 )
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Alcohol Research Programs	000	1	8/2/2022	NEW	$217,063
														Subtotal = $217,063

Grand Total All Awards = $396,376

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Role of GluN2A and MMPs in the CeA in Dependence-Induced Escalation of Etoh Drinking

Award Number: R21AA030159

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: 08/02/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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