Partial And Full Deletion Of Nicotinic Acetylcholine Receptor Alpha 4 And Beta 2 Subunits Reduces Sensitivity To Acute Nicotine Administration And Development Of Tolerance Following Chronic Nicotine Administration

The diversity of nicotinic cholinergic receptor (nAChR) subunits underlies the complex responses to nicotine. Mice differing in the expression of alpha 4 and beta 2 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 alpha 4, beta 2 or both nAChR subunits reduced the sensitivity of mice to acute nicotine administration. This reduced sensitivity was gene dose-dependent. Modification of alpha 4 subunit expression elicited a greater reduction in sensitivity than the modification of beta 2 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 (alpha 4(++)and beta 2(++)) developed measurable tolerance for all four tests. Heterozygotes (alpha 4(+-), beta 2(+-)and alpha 4(+-)/beta 2(+-)) developed tolerance for only Y-maze crossings and body temperature. Null mutants (alpha 4(- -)and beta 2(- -)) did not become tolerant. However, following chronic treatment with 4.0 mg/kg/h nicotine, wild type, alpha 4(+-)and alpha 4(- -)mice displayed increased Y-maze crossings following acute administration of 0.5 mg/kg nicotine that may reflect the activity of alpha 6 beta 2*-nAChR. These results confirm the importance of the alpha 4 and beta 2 nAChR subunits in mediating acute and chronic effects of nicotine on locomotion and body temperature in the mouse. Copyright (c) 2020 Wolters Kluwer Health, Inc. All rights reserved.