Chronic treatment with varenicline changes expression of four nAChR binding sites in mice

- Regulation of nAChR binding sites by chronic treatment with varenicline ± nicotine.
- Varenicline promotes up-regulation of α4β2-nAChR sites, similar to nicotine.
- Varenicline promotes more up-regulation of non-α4β2-nAChR sites than nicotine.
- Varenicline promotes more up-regulation of α7-nAChR sites than nicotine.
- Varenicline promotes down-regulation of α6β2 sites, similar to nicotine.

IntroductionChronic 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.MethodsUsing 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.ResultsThe 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.ConclusionsEffects 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.