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

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $549,983

## Abstract

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*-nA...

## Key facts

- **NIH application ID:** 10600540
- **Project number:** 7R01DA042749-06
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PAUL WHITEAKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $549,983
- **Award type:** 7
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600540

## Citation

> US National Institutes of Health, RePORTER application 10600540, Relevance of α-Conotoxin MII Sensitive Nicotinic Receptor Subtypes to Nicotine Addiction (7R01DA042749-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10600540. Licensed CC0.

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