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. 2015 Dec:99:142-55.
doi: 10.1016/j.neuropharm.2015.07.019. Epub 2015 Jul 17.

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

Michael J Marks  1 , Heidi C O'Neill  2 , Kelly M Wynalda-Camozzi  3 , Nick C Ortiz  4 , Emily E Simmons  5 , Caitlin A Short  6 , Christopher M Butt  7 , J Michael McIntosh  8 , Sharon R Grady  9
Affiliations

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

Michael J Marks et al. Neuropharmacology. 2015 Dec.

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.

Keywords: Chronic treatment; Cytisine (PubChem CID: 10235); Epibatidine (PubChem CID: 3073763); Nicotine; Nicotine (PubChem CID: 942); Nicotinic receptors; Varenicline; Varenicline (PubChen CID: 5310966).

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Figures

Figure 1
Figure 1
Upregulation of α4β2*-nAChR by chronic treatment with varenicline. Mice were treated with the indicated doses of varenicline as mg/kg/hr by constant infusion for 10 days. After 24 hr of withdrawal, brains were dissected and cytisine-sensitive 125I-epibatidine binding to membrane preparations of the indicated regions were determined. * indicates significantly different from saline control by one-way ANOVA. Region code: TH, thalamus; CX, cortex; ST, striatum; HP, hippocampus.
Figure 2
Figure 2
Tolerance tests after various chronic treatments. Mice were treated with 0.12 mg/kg/hr varenicline, 1 mg/kg/hr nicotine or the combination by constant infusion for 10 days followed by 24 hr withdrawal before tolerance to the indicated doses of nicotine was measured.
Figure 3
Figure 3
Comparison of effects of treatments on various subtypes of nAChR. N=6 mice/group. Panels A, B, C compare cytisine-sensitive [125I]-epibatidine binding, representing α4β2*-nAChR (white symbols) as % change from saline-treated mice. Panels D, E, F compare cytisine-resistant [125I]-epibatidine binding, representing a mixture of non- α4β2* heteromeric subtypes that differ among regions. These subtypes are color-coded as follows: α4β2 white, α3β4 pink, α6β2 blue, α3β2 + α6β2 green, α2 yellow, α7 gray. Panels G, H, I compare [125I]-α-bungarotoxin binding, representing α7-nAChR (gray symbols), and panels J, K, L compare [125I]-α-conotoxin MII binding, color-coded as above. Treatment comparisons are the same across rows; A, D, G, J compare treatments with nicotine alone and varenicline alone; B, E, H, K compare nicotine alone to nicotine + varenicline; and C, F, I, L compare varenicline alone to nicotine + varenicline. For all plots dotted lines indicate no change from saline, and dashed line indicates equivalent changes by the two treatments being compared.
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