Characterization of Spontaneous and Precipitated Nicotine Withdrawal in the Mouse

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-␤-erythroidine, and methyllycaconitine) suggest the involvement of several nicotinic subtypes such as ␣3␤4*, ␣4␤2*, and ␣7 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.

β2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning

“…This result supports previous research that has shown that somatic nicotine withdrawal symptoms are not present in mice that are withdrawn from 6 mg/kg/day nicotine (Damaj, Kao, & Martin, 2003).…”

“…For instance, DHβE-precipitated withdrawal produced limited somatic signs of nicotine withdrawal with higher doses of nicotine (Damaj et al, 2003). However, DHβE antagonizes both β2 and β4-containing nAChRs (Harvey et al, 1996;Williams & Robinson, 1984) so it is unclear if the DHβE-precipitated somatic withdrawal symptoms were associated with β2 or β4-containing nAChRs.…”

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…increased grooming, scratching, or shaking) in rats or mice that occur following spontaneous withdrawal or nAChR antagonist-precipitated withdrawal [28,77,103,102]. Additionally, mice withdrawn from chronic nicotine have been evaluated using the elevated plus maze, in which the percentage of time spent on the open arms of the maze serves as a measure of anxiety [28,77]. Mice withdrawn from nicotine spend less time on the open arms relative to saline controls, indicating increased anxiety [28,77].…”

“…Additionally, mice withdrawn from chronic nicotine have been evaluated using the elevated plus maze, in which the percentage of time spent on the open arms of the maze serves as a measure of anxiety [28,77]. Mice withdrawn from nicotine spend less time on the open arms relative to saline controls, indicating increased anxiety [28,77]. Furthermore, nicotine withdrawal-related deficits in contextual learning have been evaluated in mice [33,30,132,133].…”

Tobacco/nicotine and endogenous brain opioids

“…Other studies indicate that rats receiving chronic infusion of nicotine (6 mg/kg/day) over a 28-day period exhibit analgesia with development of tolerance, in some pain tests (Carstens et al, 2001;Zbuzek and Chin, 1994). Noteworthy is the fact that spontaneous or precipitated withdrawal from chronic nicotine administration (24 mg/kg/day for 14 days) produced hyperalgesia in mice (Damaj et al, 2003). Kishioka et al (2006) measured serum corticosterone levels in ICR mice as an index of "cross-talk" between nicotine and the opioid system.…”