Genotype Influences the Development of Tolerance to Nicotine in

Previous studies have demonstrated that chronic infusion of DBA/2 inbred mice with nicotine results in a dose- and time-dependent tolerance to many ofthe effects elicited by a challenge dose of nicotine. This tolerance was paralleled by increases in the number of brain nicotinic receptors measured with L-[3H] nicotine and a-[125l]bungarotoxin binding, suggesting that recap-tor up-regulation may underlie tolerance to nicotine. The studies reported here assessed the development of tolerance to nicotine in five inbred mouse strains that differ markedly in sensitivity to acute doses of nicotine. Mica were infused with nicotine doses ranging between 0 and 6 mg/kg/hr for 10 days and were tested for sensitivity to nicotine using several tests 2 hr after infusion was stopped. Some mouse strains, such as the C57BL/6, de-veloped tolerance to nicotine, as measured by shifts to the right of dose-response curves, at the lowest infusion doses, wherea