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Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance

Award Number: R21AA027636
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: 01/15/2020
PERIOD OF PERFORMANCE END DATE: 09/09/2022

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Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance - SUMMARY Large conductance, voltage- and calcium-activated (BK) channels are a molecular target of ethanol. Our data indicate that ethanol-induced activation of BK channels facilitates the escalation of voluntary ethanol consumption in mice made dependent to ethanol. We therefore hypothesize that molecular adaptations resulting from chronic activation of BK channels by ethanol facilitate the progression to dependence, possibly by lowering ethanol sensitivity. Accordingly, our project aims to elucidate the molecular identity of BK-dependent adaptations (Aim 1, R21 phase) and to test their functional implication in the transition to dependence (Aim 2, R33 phase) and in the control of ethanol sensitivity (Aim 3, R33 phase). We will take advantage of a knockin mouse expressing BK channels that are insensitive to ethanol but function normally otherwise to identify molecular adaptations to chronic ethanol that selectively result from the action of ethanol on BK channels. Molecular adaptations that emerge in brain regions relevant to the motivational and affective effects of ethanol (ventral tegmental area, amygdala, prelimbic prefrontal cortex, and habenula) will be examined in a well-validated mouse model of ethanol dependence. We will leverage the unprecedented sensitivity and accuracy of data-independent acquisition mass spectrometry to quantify changes in protein abundance across the entire proteome. Furthermore, we will implement weighted correlation network analysis to identify proteins that are the most likely to drive concerted changes in abundance across modules of co-expressed proteins. Nine of these proteins will be selected at the end of the R21 phase for functional analysis during the R33 phase. We will use virally mediated RNA interference to knock down candidate proteins in targeted brain regions and evaluate the influence of these proteins on the time-course, amplitude and persistence of drinking escalation in ethanol-dependent mice. We predict that some of the proteins controlling drinking escalation will also control acute sensitivity to ethanol, such that their up- or down-regulation in ethanol-dependent mice would progressively decrease sensitivity to ethanol. Accordingly, we will also examine the impact of local protein knockdown on the reinforcing and anxiolytic effects of ethanol. Altogether, the proposed experiments are designed to identify novel molecular determinants of vulnerability to alcohol use disorders. Our proposal is relevant to the focus of FOA PAR-18-659 because the proteins identified in this project may pinpoint molecular mechanisms underlying differential sensitivity to alcohol in the human population.


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: 2023 ( Subtotal = -$57,883 )
2023	2021	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	2	7/10/2023	NON-COMPETING CONTINUATION	-$57,883
														Subtotal = -$57,883

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	2	9/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $225,932 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	2	2/23/2021	NON-COMPETING CONTINUATION	$22,594
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	2	12/16/2020	NON-COMPETING CONTINUATION	$203,338
														Subtotal = $225,932

Issue Date FY: 2020 ( Subtotal = $247,556 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	1	1/15/2020	NEW	$247,556
														Subtotal = $247,556

Grand Total All Awards = $415,605

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Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance

Award Number: R21AA027636

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: 01/15/2020

PERIOD OF PERFORMANCE END DATE: 09/09/2022

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