Nicotine physical dependence and tolerance in the mouse following chronic oral administration.
BACKGROUND
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).


OBJECTIVE
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.
Grabus
Sheri D
SD
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Campus, PO Box 980613, Richmond, VA 23298-0613, USA. sdgrabus@vcu.edu
Martin
Billy R
BR
Batman
Angela M
AM
Tyndale
Rachel F
RF
Sellers
Edward
E
Damaj
M Imad
MI
D000284:Administration, Oral; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage* / Q000633:toxicity; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D011978:Receptors, Nicotinic; D009538:Nicotine