RT Journal Article
SR Electronic
T1 Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 526
OP 534
DO 10.1124/jpet.103.054908
VO 307
IS 2
A1 M. I. Damaj
A1 W. Kao
A1 B. R. Martin
YR 2003
UL http://jpet.aspetjournals.org/content/307/2/526.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics