Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.
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.
Tapper
Andrew R
AR
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
McKinney
Sheri L
SL
Nashmi
Raad
R
Schwarz
Johannes
J
Deshpande
Purnima
P
Labarca
Cesar
C
Whiteaker
Paul
P
Marks
Michael J
MJ
Collins
Allan C
AC
Lester
Henry A
HA
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
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