A COMPARISON OF THE EFFECTS OF CHRONIC NICOTINE INFUSION ON TOLERANCETO NICOTINE AND CROSS-TOLERANCE TO ETHANOL IN LONG-SLEEP AND SHORT-SLEEP MICE

Several recent studies suggest that common genes regulate sensitivity to an acute dose of ethanol and nicotine. The studies reported here at tempted to determine whether common genes regulate the development of cross-tolerance between these drugs. Long-sleep (LS) and short-sleep ( SS) mice, which were selectively bred fro differential sensitivity to ethanol as measured by duration of ethanol-induced anesthesia (sleep t ime), were used in this study. The mice were infused i.v. with saline (control) or one of several doses of nicotine (0.5-4.0 mg kg-1 hr-1) f or 10 days. The LS mice were more sensitive to the acute actions of ni cotine than were the SS and they developed more tolerance to nicotine. LS mice were tolerant to nicotine as measured by all four of the beha vioral and physiological tests used but this tolerance was readily see n only after treatment with the highest infusion dose. The SS mice dev eloped some tolerance to nicotine but this effect was less than that s een in the LS, was restricted to two of the tests (Y-maze crosses and body temperature) and was seen only after treatment with the 4.0-mg kg -1 hr-1 dose of nicotine. The LS mice developed cross-tolerance to eth anol as measured by the Y-maze crosses and the heart rate and body tem perature tests. Cross-tolerance to ethanol was not seen in the LS mice for the Y-maze rears and sleep-time tests. Almost no evidence for cro ss-tolerance to ethanol was seen in nicotine-infused SS mice. Chronic nicotine infusion elicited similar changes in [H-3]nicotine binding in eight brain regions obtained from the LS and SS mice but, unlike seve ral inbred mouse strains, the change in [H-3]nicotine binding did not parallel in a dose-dependent fashion the development of tolerance to n icotine. Thus, the LS mice are more sensitive to an acute dose of nico tine and develop more tolerance to nicotine and more cross-tolerance t o ethanol than do the SS mice but these differences are not explained by differences in nicotinic receptor binding in the brain.