Nicotine physical dependence and tolerance in the mouse following chronic oral administration
- 390 Downloads
Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e. through the use of receptor knockouts).
The goals of the present study were to establish mouse models of nicotine dependence and tolerance.
Mice were chronically exposed to nicotine (0–200 μg/ml) in their drinking solution and assayed for plasma nicotine and cotinine levels, withdrawal signs following nicotine cessation (spontaneous withdrawal) or nicotinic antagonist administration (precipitated withdrawal), or nicotine tolerance. Dependence assays included somatic sign observations (paw tremors, backing and head shakes), tail-flick, plantar stimulation, elevated plus-maze and spontaneous activity. Tolerance was assayed using tail-flick, hot-plate and body temperature tests.
Plasma nicotine and cotinine levels were elevated during oral nicotine exposure (15.85 ng/ml and 538.00 ng/ml, respectively) and quickly declined following nicotine cessation (<1 ng/ml and <2 ng/ml, respectively), providing evidence that the oral route was pharmacologically relevant. Nicotine withdrawal increased numbers of somatic signs (spontaneous and mecamylamine-precipitated withdrawal) and/or hyperalgesia (spontaneous withdrawal only). Chronic nicotine exposure also produced tolerance, as indicated by reduced responsivity to acute nicotine in assays of analgesia and hypothermia.
These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal.
KeywordsNicotine Withdrawal Dependence Tolerance Mice
- Atwell L, Jacobson AE (1978) The search for less harmful analgesics. Lab Anim 7:42–47Google Scholar
- D’Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 107:385–939Google Scholar
- Okamoto M, Kita T, Okuda H, Nakashima T (1992) Tolerance to the convulsions induced by daily nicotine treatment in rats. Jpn J Pharmacol 594:449–455Google Scholar
- Pietilä K, Laakso I, Ahtee L (1995) Chronic oral nicotine administration affects the circadian rhythm of dopamine and 5-hydroxytryptamine metabolism in the striata of mice. Naunyn Schmiedeberg’s Arch Pharmacol 353:110–115Google Scholar
- Pietilä K, Lähde T, Attila M, Ahtee L, Nordberg A (1998) Regulation of nicotinic receptors in the brain of mice withdrawn from chronic oral nicotine treatment. Naunyn Schmiedeberg’s Arch Pharmacol 357:176–182Google Scholar