title: Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.
abstract: The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with a4 nicotinic subunits containing a single point mutation, Leu9' --> Ala9' in the pore-forming M2 domain, rendering a4* receptors hypersensitive to nicotine. Selective activation of a4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of a4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
authors.forename: Sheri L
authors.initials: SL
authors.lastname: McKinney
authors.forename: Raad
authors.initials: R
authors.lastname: Nashmi
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwarz
authors.forename: Purnima
authors.initials: P
authors.lastname: Deshpande
authors.forename: Cesar
authors.initials: C
authors.lastname: Labarca
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: Allan C
authors.initials: AC
authors.lastname: Collins
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
mesh_terms: D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D001392:Azocines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004361:Drug Tolerance; D007930:Leucine; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D017354:Point Mutation; D011725:Pyridines / Q000378:metabolism; D011807:Quinolizines / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D012201:Reward; D012694:Serine; D014029:Tobacco Use Disorder / Q000378:metabolism*; D015854:Up-Regulation; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium; D007930:Leucine; D009538:Nicotine; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012694:Serine; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine