A COMPARISON OF THE DEVELOPMENT OF TOLERANCE TO ETHANOL AND CROSS-TOLERANCE TO NICOTINE AFTER CHRONIC ETHANOL TREATMENT IN LONG-SLEEP AND SHORT-SLEEP MICE

Previous studies have shown that inbred mouse strains differ in the de velopment of tolerance to both nicotine and ethanol, indicating that g enetic factors regulate tolerance development. Those mouse strains tha t are most sensitive to an acute challenge dose of either drug develop the most tolerance to that drug. The ethanol-sensitive long-sleep (LS ) mice are more sensitive to several behavioral and physiological effe cts of nicotine than are the ethanol-resistant short-sleep (SS) mice. The experiments reported here assessed whether the LS and SS mice deve lop tolerance to ethanol after chronic treatment with ethanol-containi ng liquid diets and whether cross-tolerance to nicotine also developed . Tolerance and cross-tolerance were measured by assessing the effects of acute challenge doses of drug on Y-maze crossing and rearing activ ities, heart rate and body temperature. The LS mice developed toleranc e to ethanol's effects on three of the four measures and were cross-to lerant to nicotine on all of the measures. In contrast, the SS mice de veloped tolerance to ethanol for only two of the measures, but failed to develop cross-tolerance to any action of nicotine. These findings s upport the hypothesis that ethanol and nicotine share sites of action and that common genes regulate responses to these two drugs. Evidence suggests that tolerance to nicotine may be related to an up-regulation of brain nicotinic receptors, at least in some inbred mouse strains, but chronic ethanol treatment did not reproducibly change either [H-3] nicotine or alpha-[I-125]bungaro-toxin binding. Therefore, other mecha nisms must underlie the tolerance and cross-tolerance that was seen.