title: Varenicline blocks β2*-nAChR-mediated response and activates β4*-nAChR-mediated responses in mice in vivo.
abstract: BACKGROUND
  The smoking cessation aid, varenicline, has higher affinity for the alpha4beta2-subtype of the nicotinic acetylcholine receptor (α4β2*-nAChR) than for other subtypes of nAChRs by in vitro assays. The mechanism of action of acute varenicline was studied in vivo to determine (a) subtype activation associated with physiological effects and (b) dose relationship as an antagonist of nicotine.
  
  
  METHODS
  Acute doses of saline, nicotine, and varenicline were given to mice, and locomotor depression and hypothermia were measured. Subunit null mutant mice as well as selective antagonists were used to study mode of action of varenicline as an agonist. Varenicline as an antagonist of nicotine was also investigated.
  
  
  RESULTS
  Varenicline evokes locomotor depression and hypothermia at higher doses than necessary for nicotine. Null mutation of the α7- or β2-nAChR subunit did not decrease the effectiveness of varenicline; however, null mutation of the β4 subunit significantly decreased the magnitude of the varenicline effect. Effects of the highest dose studied were blocked by mecamylamine (general nAChR antagonist) and partially antagonized by hexamethonium (largely peripheral nAChR antagonist). No significant block was seen with ondansetron antagonist of 5-hydroxytryptamine 3 receptor. Using a dose of nicotine selective for β2*-nAChR subtype effects with these tests, dose-dependent antagonism by varenicline was seen. Effective inhibitory doses were determined and appear to be in a range consistent with binding affinity or desensitization of β2*-nAChRs.
  
  
  CONCLUSIONS
  Varenicline acts as a functional antagonist of β2*-nAChRs, blocking certain effects of nicotine. At higher doses, varenicline is an agonist of β4*-nAChRs producing physiological changes in mice.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Ortiz
authors.forename: Heidi C
authors.initials: HC
authors.lastname: O'Neill
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D018738:Hexamethonium / Q000494:pharmacology; D007035:Hypothermia / Q000139:chemically induced; D020128:Inhibitory Concentration 50; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017294:Ondansetron / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018738:Hexamethonium; D008464:Mecamylamine; D009419:Nerve Tissue Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D017294:Ondansetron; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D000068580:Varenicline; C486720:Chrnb4 protein, mouse