title: Differential expression of the beta4 neuronal nicotinic receptor subunit affects tolerance development and nicotinic binding sites following chronic nicotine treatment.
abstract: The role of neuronal nicotinic acetylcholine receptors (nAChR) containing the β4 subunit in tolerance development and nicotinic binding site levels following chronic nicotine treatment was investigated. Mice differing in expression of the β4-nAChR subunit [wild-type (β4(++)), heterozygote (β4(+-)) and null mutant (β4(--))] were chronically treated for 10 days with nicotine (0, 0.5, 1.0, 2.0 or 4.0mg/kg/h) by constant intravenous infusion. Chronic nicotine treatment elicited dose-dependent tolerance development. β4(--) mice developed significantly more tolerance than either β4(++) or β4(+-) mice which was most evident following treatment with 4.0mg/kg/h nicotine. Subsets of [(125)I]-epibatidine binding were measured in several brain regions. Deletion of the β4 subunit had little effect on initial levels of cytisine-sensitive [(125)I]-epibatidine binding (primarily α4β2-nAChR sites) or their response (generally increased binding) to chronic nicotine treatment. In contrast, β4 gene-dose-dependent decreases in expression 5IA-85380 resistant [(125)I]-epibatidine binding sites (primarily β4*-nAChR) were observed. While these β4*-nAChR sites were generally resistant to regulation by chronic nicotine treatment, significant increases in binding were noted for habenula and hindbrain. Comparison of previously published tolerance development in β2(--) mice (less tolerance) to that of β4(--) mice (more tolerance) supports a differential role for these receptor subtypes in regulating tolerance following chronic nicotine treatment.
authors.affiliation: Institute for Behavioral Genetics, 447 UCB, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: erin.meyers@gmail.com.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Meyers
authors.affiliation: Institute for Behavioral Genetics, 447 UCB, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: esteban.loetz@colorado.edu.
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Loetz
authors.affiliation: Institute for Behavioral Genetics, 447 UCB, University of Colorado Boulder, Boulder, CO 80309, USA; Department of Psychology and Neuroscience, 345 UCB, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: marksm@colorado.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D007457:Iodine Radioisotopes; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D011725:Pyridines; D011807:Quinolizines / Q000494:pharmacology; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007457:Iodine Radioisotopes; D009419:Nerve Tissue Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C486720:Chrnb4 protein, mouse; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine
keywords: Beta4 null mutant mice; Chronic nicotine treatment; Cytisine; Epibatidine binding; Nicotine tolerance; Nicotinic acetylcholine receptor