Cited by 222Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyPrenatal Substance Exposure Effects

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Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse

Damaj, M.I., Kao, W., Martin, B.R.·2003·The Journal of Pharmacology and Experimental Therapeutics

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Abstract

The nicotine withdrawal syndrome was validated and characterized in the mouse using both somatic and affective measures after infusion with nicotine daily via subcutaneous minipumps. The influence of dose, duration of infusion, and repeated withdrawal as well as the contribution of genetic factors were investigated. We then characterized the contribution of nicotinic receptor and site mechanisms to withdrawal signs using various nicotinic antagonists. Our results showed that spontaneous nicotine withdrawal increased the number of somatic signs, decreased the time spent in open arms of the plus-maze test, and induced hyperalgesia. The effect was dose-dependent in all measures with no significant changes at the lowest dose of nicotine (6 mg/kg/day). Withdrawal signs were prominent shortly after pump removal and remained prominent through day 3 or 4. The results with the different antagonists (mecamylamine, dihydro-beta-erythroidine, and methyllycaconitine) suggest the involvement of several nicotinic subtypes such as alpha3beta4*, alpha4beta2*, and alpha7 in nicotine withdrawal. Increasing the duration of nicotine exposure (from 7 to 60 days) and the total nicotine exposure (increasing doses of infusing) augmented the severity of nicotine withdrawal signs. The withdrawal severity of nicotine differs between C57/BL and 129/SvEv inbred mice with nicotine withdrawal in C57 being more severe than in the 129 strain. In summary, our present results suggest that withdrawal from nicotine can be modulated by genetic factors, daily nicotine intake, duration of nicotine exposure, and withdrawal history. The present study demonstrates that our mouse nicotine withdrawal model will be useful for studying the pharmacological, biochemical, and genetic mechanisms involved in nicotine dependence.

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Authors: Damaj, M. I., Kao, W., & Martin, B. R.
Affiliations: Virginia Commonwealth University (US)
ORCID: Damaj, M.I.
Venue: The Journal of Pharmacology and Experimental Therapeutics
Publisher: Elsevier BV
Published: 2003-11
Volume: 307
Issue: 2
Pages: 526-534
ISSN: 0022-3565 (ISSN-L)
DOI: 10.1124/jpet.103.054908
OpenAlex: W2112994833
Cited by: 222
References: 24
Citations by year: 2026: 5 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 3 · 2021: 12 · 2020: 14 · 2019: 12 · 2018: 14 · 2017: 7 · 2016: 15 · 2015: 12 · 2014: 12 · 2013: 14 · 2012: 11
FWCI: 3.56
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Drug Abuse (DA 05274)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
Keywords: nicotine withdrawal, nicotine dependence, spontaneous withdrawal, nicotinic acetylcholine receptors, nicotinic receptor subtypes, alpha3beta4 nicotinic receptor, alpha4beta2 nicotinic receptor, alpha7 nicotinic acetylcholine receptor, nicotinic antagonists, mecamylamine, dihydro-beta-erythroidine, methyllycaconitine, hyperalgesia, anxiety-like behavior, inbred mouse strains
MeSH terms: Animals, Disease Models, Animal, Male, Mecamylamine, Mice, Inbred ICR, Nicotine, Substance Withdrawal Syndrome, Time Factors, Tobacco Use Disorder, Nicotinic Antagonists, Mice

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Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse

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