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Research ArticleNEUROPHARMACOLOGY

Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse

M. I. Damaj, W. Kao and B. R. Martin
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 526-534; DOI: https://doi.org/10.1124/jpet.103.054908
M. I. Damaj
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W. Kao
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B. R. Martin
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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-β-erythroidine, and methyllycaconitine) suggest the involvement of several nicotinic subtypes such as α3β4*, α4β2*, and α7 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.

Footnotes

  • DOI: 10.1124/jpet.103.054908.

  • This work was supported by National Institute on Drug Abuse Grant DA-05274.

  • ABBREVIATIONS: MLA, methyllycaconitine; ANOVA, analysis of variance; nAChR, nicotinic acetylcholine receptor.

    • Received May 22, 2003.
    • Accepted July 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleNEUROPHARMACOLOGY

Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse

M. I. Damaj, W. Kao and B. R. Martin
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 526-534; DOI: https://doi.org/10.1124/jpet.103.054908

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Research ArticleNEUROPHARMACOLOGY

Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse

M. I. Damaj, W. Kao and B. R. Martin
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 526-534; DOI: https://doi.org/10.1124/jpet.103.054908
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