title: Chronic treatment with varenicline changes expression of four nAChR binding sites in mice.
abstract: BACKGROUND
  Chronic treatment with nicotine is known to increase the α4β2-nAChR sites in brain, to decrease α6β2-nAChR sites and to have minimal effect on α3β4-and α7-nAChR populations. Varenicline is now used as a smoking cessation treatment, with and without continued smoking or nicotine replacement therapy. Varenicline, like nicotine, upregulates the α4β2-nAChR sites; however, it is not known whether varenicline treatment changes expression of the other nAChR subtypes.
  
  
  METHODS
  Using a mouse model, chronic treatments (10 days) with varenicline (0.12  mg/kg/h) and/or nicotine (1 mg/kg/hr), alone or in combination, were compared for plasma and brain levels of drugs, tolerance to subsequent acute nicotine and expression of four subtypes of nAChR using autoradiography.
  
  
  RESULTS
  The upregulation of α4β2-nAChR sites elicited by chronic varenicline was very similar to that elicited by chronic nicotine. Treatment with both drugs somewhat increased up-regulation, indicating that these doses were not quite at maximum effect. Similar down-regulation was seen for α6β2-nAChR sites. Varenicline significantly increased both α3β4-and α7-nAChR sites while nicotine had less effect on these sites. The drug combination was similar to varenicline alone for α3β4-nAChR sites, while for α7 sites the drug combination was less effective than varenicline alone. Varenicline had small but significant effects on tolerance to acute nicotine.
  
  
  CONCLUSIONS
  Effects of varenicline in vivo may not be limited to the α4β2*-nAChR subtype. In addition, smoking cessation treatment with varenicline may not allow receptor numbers to be restored to baseline and may, in addition, change expression of other receptor subtypes.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA. Electronic address: marksm@colorado.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: heidi.oneill@colorado.edu.
authors.forename: Heidi C
authors.initials: HC
authors.lastname: O'Neill
authors.affiliation: DSM Nutritional Products Biological Sciences 4, Boulder, CO, USA. Electronic address: Kelly.Wynalda@DSM.com.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Wynalda-Camozzi
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: nick.ortiz@colorado.edu.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Ortiz
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: emily.evans.simmons@gmail.com.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Simmons
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: caitlin.a.short@gmail.com.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Short
authors.affiliation: DSM Nutritional Products Biological Sciences 4, Boulder, CO, USA. Electronic address: chris.butt@dsm.com.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Butt
authors.affiliation: Departments of Biology and Psychiatry, University of Utah, Salt Lake City, UT, USA. Electronic address: mcintosh.mike@gmail.com.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: sharon.grady@colorado.edu.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
mesh_terms: D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D061485:Tobacco Use Cessation Devices; D000068580:Varenicline / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D000068580:Varenicline
keywords: Chronic treatment; Cytisine (PubChem CID: 10235); Epibatidine (PubChem CID: 3073763); Nicotine; Nicotine (PubChem CID: 942); Nicotinic receptors; Varenicline; Varenicline (PubChen CID: 5310966)