Nicotine-induced tolerance and receptor changes in four mouse strains.

The effects of chronic infusion of 3.0 mg/kg/hr of nicotine on the behavioral responses of four mouse strains (C3H, C57BL, BALB and DBA) to challenge doses of nicotine and on the levels of cholinergic receptors and enzymes were determined. Mice of the C57BL, BALB and DBA strains developed tolerance to the effects of nicotine on Y-maze activity, Y-maze rearing and body temperature. The C3H mice did not exhibit any evidence of tolerance to the effects of nicotine on these measures, but this strain did show tolerance to the effects of nicotine on acoustic startle response. None of the strains developed tolerance to the effects of nicotine on respiration rate, and only the BALB mice demonstrated tolerance to nicotine-induced bradycardia. Chronic nicotine treatment also elicited changes in putative brain nicotinic receptors. Increased binding of L-[3H]nicotine was seen in six brain regions in all four mouse strains. The changes in binding were similar for all the strains. The binding of alpha-[125I]bungarotoxin was also elevated in the four mouse strains, and modest differences among the strains were evident in this measure, with the C3H strain showing the smallest increases in four of the six brain regions. Chronic nicotine treatment did not alter brain muscarinic receptors, as measured with L-[3H]quinuclidinyl benzilate binding, nor were the activities of acetylcholinesterase or choline acetyltransferase altered, except that a small change in hippocampal choline acetyltransferase activity may have occurred. These results indicate that tolerance to nicotine is regulated by genetic factors and that changes in brain nicotinic receptor numbers are not sufficient to explain the development of tolerance.