Michael J Marks1, Heidi C O'Neill2, Kelly M Wynalda-Camozzi3, Nick C Ortiz4, Emily E Simmons5, Caitlin A Short6, Christopher M Butt7, J Michael McIntosh8, Sharon R Grady9. 1. 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. 2. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: heidi.oneill@colorado.edu. 3. DSM Nutritional Products Biological Sciences 4, Boulder, CO, USA. Electronic address: Kelly.Wynalda@DSM.com. 4. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: nick.ortiz@colorado.edu. 5. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: emily.evans.simmons@gmail.com. 6. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: caitlin.a.short@gmail.com. 7. DSM Nutritional Products Biological Sciences 4, Boulder, CO, USA. Electronic address: chris.butt@dsm.com. 8. Departments of Biology and Psychiatry, University of Utah, Salt Lake City, UT, USA. Electronic address: mcintosh.mike@gmail.com. 9. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. Electronic address: sharon.grady@colorado.edu.
Abstract
INTRODUCTION: 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.
INTRODUCTION: 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.
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