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Spectral Confocal Imaging of Fluorescently tagged Nicotinic Receptors in Knock-in Mice with Chronic Nicotine Administration
Published on: February 10, 2012
Nicotine physical dependence and tolerance in the mouse following chronic oral administration
Sheri D Grabus1, Billy R Martin, Angela M Batman
1Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Campus, PO Box 980613, Richmond, VA 23298-0613, USA. sdgrabus@vcu.edu
Rationale:
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).
Objectives:
The goals of the present study were to establish mouse models of nicotine dependence and tolerance.
Methods:
Mice were chronically exposed to nicotine (0-200 mug/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.
Results:
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.
Conclusions:
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.
Insights
Mice developed nicotine dependence and tolerance through chronic oral exposure. This establishes a mouse model for studying the effects of nicotine on the brain and behavior.
Area of Science:
- Neuroscience
- Pharmacology
- Animal Models
Background:
- Nicotine dependence and tolerance are well-documented in rats.
- Few studies have established these processes in mice, limiting research into specific nicotinic receptor subtypes.
- Mouse models are crucial for genetic studies, such as using receptor knockouts.
Purpose of the Study:
- To establish reliable mouse models for nicotine dependence and tolerance.
- To validate the oral route of nicotine administration for these studies.
- To provide a foundation for future research on nicotinic receptor involvement.
Main Methods:
- Mice received chronic oral nicotine exposure.
- Assessed plasma nicotine and cotinine levels.
- Evaluated withdrawal signs (spontaneous and precipitated) and tolerance using behavioral and physiological tests.
Main Results:
- Oral nicotine administration led to detectable plasma levels, confirming route relevance.
- Chronic nicotine exposure induced significant somatic signs of withdrawal and hyperalgesia.
- Mice exhibited tolerance to nicotine's analgesic and hypothermic effects.
Conclusions:
- Chronic oral nicotine administration effectively produces dependence and tolerance in mice.
- The findings support the use of this mouse model for further investigation.
- Nicotine dependence likely involves multiple nicotinic receptor subtypes.
