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A Novel Pharmacotherapy for Alcoholism: Evaluation of Reward, Aversion, Compulsivity, Withdrawal & Reinstatement

Award Number: R01AA026281
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Alcohol use disorders (AUD) place an enormous burden on our society. In addition to their psychological and social toll, it is estimated that AUDs cost the US economy $249 billion in the year 2010 alone. Although there are already several effective behavioral and pharmacological treatments, there is an urgent need for new pharmacotherapies that act via novel mechanisms. We have recently shown that inhibitors of the enzyme Glyoxalase 1 (GLO1) reduce voluntary ethanol drinking in mice (McMurray, et al 2017a). GLO1 is a cytosolic enzyme that metabolizes methylglyoxal (MG). MG is a non-enzymatic side product of glycolysis and is therefore present in all cells. Thus, GLO1 activity is inversely related to MG concentration. We have previously shown that transgenic overexpression of GLO1 increases anxiety-like behavior in mice and decreases MG concentrations in the brain. Reciprocally, we showed that direct administration of MG, genetic knockdown of Glo1 or inhibition of GLO1 using a small molecule inhibitor all decrease anxiety-like behavior and increase MG concentrations in brain. We found that even higher doses of MG produced locomotor depression, ataxia and hypothermia; taken together these data suggested that MG might be acting through GABA-A receptors. Indeed, using a patch clamp procedure, we found that MG is a competitive partial agonist at GABA-A receptors. We also showed that MG is highly selective: it does not activate GABA-B receptors, other ligand gated ion channels or voltage gated ion channels. More recently, we have shown that GLO1 inhibition has antidepressant-like effects, suggesting that GLO1 inhibitors might treat anxiety and depression, both of which are comorbid with AUD. Given the importance of GABA-A signaling in the effects of ethanol, we speculated that GLO1 and MG might also modulate ethanol-related behaviors, which led us to study the effects of GLO1 on ethanol drinking. Those studies showed that inhibition of GLO1 decreased ethanol drinking, which is the rationale for the experiments proposed in this application. We are proposing studies aimed at understanding why inhibition of GLO1 reduces voluntary ethanol drinking. In Aim 1 we will use the intracranial self-stimulation (ICSS) procedure to examine the acute and chronic effects of genetic and pharmacological manipulations of GLO1 on hedonic and anhedonic responses to ethanol in mice. In Aim 2 we will use conditioned place preference (CPP) and conditioned taste aversion (CTA) to study the effects of GLO1 on preference and aversion for ethanol in mice. Finally, in Aim 3, we will use the chronic intermittent ethanol (CIE) procedure to examine the effects of Glo1 inhibitors on acute ethanol withdrawal, compulsive-like responding for ethanol and reinstatement of ethanol seeking behavior after protracted abstinence in rats.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	11/3/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $473,081 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	5	5/26/2022	SUPPLEMENT FOR EXPANSION	$89,681
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	5/25/2022	NON-COMPETING CONTINUATION	$383,400
														Subtotal = $473,081

Issue Date FY: 2021 ( Subtotal = $383,400 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	4	4/29/2021	NON-COMPETING CONTINUATION	$383,400
														Subtotal = $383,400

Issue Date FY: 2020 ( Subtotal = $383,400 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	3	4/22/2020	NON-COMPETING CONTINUATION	$383,400
														Subtotal = $383,400

Issue Date FY: 2019 ( Subtotal = $383,400 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	4/22/2019	NON-COMPETING CONTINUATION	$383,400
														Subtotal = $383,400

Issue Date FY: 2018 ( Subtotal = $395,775 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	7/5/2018	NEW	$395,775
														Subtotal = $395,775

Grand Total All Awards = $2,019,056

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A Novel Pharmacotherapy for Alcoholism: Evaluation of Reward, Aversion, Compulsivity, Withdrawal & Reinstatement

Award Number: R01AA026281

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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