Partial and full deletion of nicotinic acetylcholine receptor α4 and ß2 subunits reduces sensitivity to acute nicotine administration and development of tolerance following chronic nicotine administration.

ABSTRACT

The diversity of nicotinic cholinergic receptor (nAChR) subunits underlies the complex responses to nicotine. Mice differing in the expression of α4 and ß2 subunits, which are most widely expressed in brain, were evaluated for the responses to acute nicotine administration on Y-maze crossings and rears, open-field locomotion and body temperature following chronic treatment with nicotine (0, 0.25, 1.0 and 4.0 mg/kg/h). Deletion or partial deletion of the α4, ß2 or both nAChR subunits reduced the sensitivity of mice to acute nicotine administration. This reduced sensitivity was gene dose-dependent. Modification of α4 subunit expression elicited a greater reduction in sensitivity than the modification of ß2 subunit expression. No measurable tolerance was observed for mice of any genotype following chronic treatment with 0.25 mg/kg/h nicotine. Modest tolerance was noted following treatment with 1.0 mg/kg/h. Greater tolerance was observed following treatment with 4.0 mg/kg/h. The extent of tolerance differed among the mice depending on genotype wild-type (α4 and ß2) developed measurable tolerance for all four tests. Heterozygotes (α4, ß2 and α4/ß2) developed tolerance for only Y-maze crossings and body temperature. Null mutants (α4 and ß2) did not become tolerant. However, following chronic treatment with 4.0 mg/kg/h nicotine, wild type, α4 and α4 mice displayed increased Y-maze crossings following acute administration of 0.5 mg/kg nicotine that may reflect the activity of α6ß2*-nAChR. These results confirm the importance of the α4 and ß2 nAChR subunits in mediating acute and chronic effects of nicotine on locomotion and body temperature in the mouse.