Journal Article

Reversal of Nicotine Withdrawal Signs Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Male Mice

Ayman K Hamouda, Asti Jackson, Deniz Bagdas and M Imad Damaj

in Nicotine and Tobacco Research

Volume 20, issue 7, pages 903-907
Published in print June 2018 | ISSN: 1462-2203
Published online August 2017 | e-ISSN: 1469-994X | DOI: https://dx.doi.org/10.1093/ntr/ntx183
Reversal of Nicotine Withdrawal Signs Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Male Mice

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Abstract

Introduction

Nicotine withdrawal symptoms are important factors in determining the relapse rate to tobacco smoking and drugs that diminish these symptoms would potentially have a higher success rate as smoking cessation aids. Unlike US Food and Drug administration approved smoke cessation aids (nicotine and varenicline) which act as nicotinic acetylcholine receptors (nAChRs) agonists, desformylflustrabromine (dFBr) acts as a nAChR positive allosteric modulator with higher selectivity to the α4β2 nAChR. In animal studies, dFBr was well tolerated and reduced intravenous nicotine self-administration. In this study, we use behavioral test in mouse model of spontaneous nicotine withdrawal to assess the effect of dFBr on nicotine withdrawal symptoms.

Methods

Spontaneous nicotine withdrawal in nicotine-dependent ICR male mice was established 18–24 h after termination (minipump removal) of 14 days infusion of nicotine. After that (day 15), spontaneous signs of nicotine withdrawal were examined in the following order: anxiety-like behaviors, somatic signs, and then hyperalgesia using previously published behavioral protocols. Fifteen minutes before withdrawal signs testing, mice received a subcutaneous acute injection of vehicle or dFBr at the doses of 0.02, 0.1, and 1 mg/kg to determine the effect of dFBr on nicotine withdrawal symptoms.

Results

dFBr produced dose-dependent reversal of nicotine withdrawal signs in mouse model of spontaneous nicotine withdrawal.

Implications

Positive allosteric modulators of nAChR such as dFBr reduce nicotine withdrawal symptoms supporting the potential clinical use of this novel class of nAChR-based therapeutics as smoking cessation aid.

Journal Article.  2786 words.  Illustrated.

Subjects: Public Health and Epidemiology ; Addictions and Substance Misuse

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