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Relevance of α-Conotoxin MII Sensitive Nicotinic Receptor Subtypes to Nicotine Addiction

Award Number: R01DA042749
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Relevance of α-Conotoxin MII Sensitive Nicotinic Receptor Subtypes to Nicotine Addiction - SUMMARY / ABSTRACT α-Conotoxin MII (α-CtxMII) selectively antagonizes α3β2*- and α6β2*-nAChR. We have previously developed α6β2*-nAChR-selective α-Ctxs to define mesolimbic α6β2*-nAChR contributions to nicotine and other drug abuse phenotypes. A lack of selective compounds, and lethality in α3 nAChR null mutant mice means virtually no α3β2*-nAChR studies have been performed. Nor have extra-limbic α6β2*-nAChR contributions to addiction- relevant behaviors been investigated extensively. Therefore, we will develop α-Ctx ligands to discriminate between, characterize, and define the roles of α3β2*- and α6β2*-nAChR. The medial habenula (MH) and interpeduncular nucleus (IPN) contain the densest CNS α3β2*-nAChR populations (which outnumber MH and IPN α6β2*-nAChR). α3β4*- and α5*-nAChR in MH and IPN support nicotine dependence but ganglionic expression of α3β4*-nAChR and lack of α5*-nAChR in orthosteric binding sites may make these problematic smoking cessation targets. To establish and differentiate MH and IPN α3β2*- and α6β2*-nAChR contributions to nicotine abuse and addiction phenotype, three Specific Aims are proposed: 1) To discover further lead α-Ctx ligands with α3β2*-nAChR selectivity by screening an existing panel of >400 novel peptides, and develop them for enhanced selectivity. We have already identified 2 α-Ctx leads with >10-fold α3β2*-nAChR selectivity over other subtypes. The most-selective leads will be developed using a novel and streamlined approach to improve α-Ctx selectivity. 2) To elucidate MH and IPN α3β2*-nAChR subunit composition. We will make radio- and fluorescence-labeled derivatives of the highly-selective peptides developed in Aim 1. Using these labeled peptides, detailed α3β2*-nAChR composition will be confirmed for the first time using nAChR subunit-null mutant mice. 3) To define the importance of MH and IPN α3β2*- and α6β2*-nAChR in nicotine reinforcement and withdrawal. We will test in rats if local infusion of the selective antagonists α-CtxMII (α3β2* & α6β2*), α- CtxPIA (α6β2*-only), or a novel α3β2*-only α-Ctx into MH, IPN or 2 more control regions a) affects motivation to work for nicotine (under a progressive ratio schedule) and b) affects spontaneous somatic and behavioral withdrawal symptoms. For Aims 2 & 3, we describe how to proceed using existing compounds in the extremely unlikely case that Aim 1 does not yield suitably α3β2*-nAChR-selective α-Ctxs. This proposal's new screening and peptide-development features will radically advance future utilization of the invaluable α-Ctx resource. The resources developed in this proposal will be vital to enable future studies probing nAChR function within the addiction-related network to which MH and IPN are extensively connected. Using our novel and potent method for engineering α-Ctx selectivity in combination with refined behavioral testing across male and female subjects greatly enhances translational impact. This proposal promises to identify and characterize α3β2*-nAChR as novel, druggable, smoking therapeutic targets, and confirm α6β2*-nAChR as a viable tobacco cessation target. These advances may produce a major impact on public health by promoting smoking cessation.


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: 2025 ( Subtotal = -$2,611 )
2025	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	6	10/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,087
2025	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	002	6	11/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$2,611
2025	2020	DIGNITY HEALTH	350 W THOMAS RD	PHOENIX	AZ	85013	MARICOPA	USA	Drug Use and Addiction Research Programs	000	4	10/17/2024	NON-COMPETING CONTINUATION	-$46,087
														Subtotal = -$2,611

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	6	11/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$124,190
2023	2020	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	4	11/13/2022	NON-COMPETING CONTINUATION	-$124,190
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	6	8/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$549,983
2022	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	5	8/17/2022	NON-COMPETING CONTINUATION	-$549,983
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $549,983 )
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	5	6/11/2021	NON-COMPETING CONTINUATION	$549,983
														Subtotal = $549,983

Issue Date FY: 2020 ( Subtotal = $553,022 )
2020	2020	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	4	6/22/2020	NON-COMPETING CONTINUATION	$553,022
														Subtotal = $553,022

Issue Date FY: 2019 ( Subtotal = $570,162 )
2019	2019	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	3	6/19/2019	NON-COMPETING CONTINUATION	$570,162
														Subtotal = $570,162

Issue Date FY: 2018 ( Subtotal = $568,289 )
2018	2018	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	2	6/27/2018	NON-COMPETING CONTINUATION	$568,289
														Subtotal = $568,289

Issue Date FY: 2017 ( Subtotal = $567,207 )
2017	2017	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	1	9/7/2017	NEW	$567,207
														Subtotal = $567,207

Grand Total All Awards = $2,806,052

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Relevance of α-Conotoxin MII Sensitive Nicotinic Receptor Subtypes to Nicotine Addiction

Award Number: R01DA042749

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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