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Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons

Award Number: R01AA025721
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: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons - Project Summary: Clear neuroadaptations occur as a result of alcohol use disorders, underlying the debilitating health risks and social problems associated with the disease. While changes in GABAergic, glutamatergic and dopaminergic neurotransmission are strongly implicated, the precise neurological mechanisms that cause enhanced susceptibility of alcohol intake and preference are not yet well understood. As a result, current treatments available to combat alcoholism are sparse and nonspecific— besides psychotherapy, detoxification and nausea-inducing, emetic drugs, there are no pharmacological targets for treating the disease. Recent studies have uncovered non-canonical GABA synthesis mediated by aldehyde dehydrogenase 1a1 (ALDH1a1) and co-release from dopaminergic midbrain neurons, and we have gathered strong evidence suggesting that this alternative GABA synthesis pathway is diminished with blood alcohol levels that are associated with binge drinking. Methodological advances now provide the opportunity to directly examine and dissect the role of this GABA pathway in acute and chronic alcohol exposure. In this proposal, we hypothesize that the balance between co-released dopamine and GABA by midbrain dopamine neurons is critical for postsynaptic striatal spiny projection neurons (SPNs). In addition, alcohol and/or its metabolic product inhibit dopaminergic GABA by impairing GABA non-canonical synthesis, ultimately perturbing the co-released GABA by dopamine neurons in the dorsal striatum, and lead to enhancement in susceptibility of alcohol intake and preference. We will employ the use of genetically modified mice and virus injections to directly examine dopamine neurons and the specific pathways involved in GABA synthesis, modulation and release. By optogenetic activation of dopamine terminals in the striatum and whole-cell patch clamp on identified principle striatal cells, our experiments will provide a high-resolution assessment of the function of dopaminergic GABAergic in normal and enhanced alcohol intake and preference conditions. Combined with imaging, electrophysiology, optogenetics, biochemistry and behavioral analysis, this proposal provides a unique, multi- faceted approach to study dopamine and GABA co-release in the basal ganglia, and the mechanisms by which chronic binge drinking alters this form of neurotransmitter release. Based on our compelling preliminary findings, we aim to 1) examine whether cell-type specific deletion of ALDH1a1 in dopamine neurons leads to enhanced alcohol preference; 2) pinpoint the mechanism underlying the inhibition of co-released GABA by alcohol; and 3) investigate alcohol modulation of functional interplay between GABA and dopamine in the striatum. Our novel initial findings and the studies proposed in this grant will close the gaps in our knowledge about GABA synthesis in dopaminergic neurons and create a new window into our understanding of synaptic mechanisms underlying enhanced alcohol intake and preference, providing better tools and earlier targets for the treatment or prevention of alcohol use 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: 2022 ( Subtotal = $0 )
2022	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Alcohol Research Programs	000	5	9/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $361,097 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Alcohol Research Programs	000	5	6/3/2021	NON-COMPETING CONTINUATION	$361,097
														Subtotal = $361,097

Issue Date FY: 2020 ( Subtotal = $360,866 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Alcohol Research Programs	000	4	5/27/2020	NON-COMPETING CONTINUATION	$360,866
														Subtotal = $360,866

Issue Date FY: 2019 ( Subtotal = $360,648 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Alcohol Research Programs	000	3	5/29/2019	NON-COMPETING CONTINUATION	$360,648
														Subtotal = $360,648

Issue Date FY: 2018 ( Subtotal = $360,431 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Alcohol Research Programs	000	2	5/10/2018	NON-COMPETING CONTINUATION	$360,431
														Subtotal = $360,431

Issue Date FY: 2017 ( Subtotal = $360,226 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Alcohol Research Programs	000	1	8/21/2017	NEW	$360,226
														Subtotal = $360,226

Grand Total All Awards = $1,803,268

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Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons

Award Number: R01AA025721

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: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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