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. 2012 Aug;342(2):327-34.
doi: 10.1124/jpet.112.194852. Epub 2012 May 1.

Varenicline is a potent partial agonist at α6β2* nicotinic acetylcholine receptors in rat and monkey striatum

Tanuja Bordia  1 , Maya Hrachova, Matthew Chin, J Michael McIntosh, Maryka Quik
Affiliations

Varenicline is a potent partial agonist at α6β2* nicotinic acetylcholine receptors in rat and monkey striatum

Tanuja Bordia et al. J Pharmacol Exp Ther. 2012 Aug.

Abstract

Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at α4β2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that α6β2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on α6β2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited α6β2* nAChR binding (K(i) = 0.12 nM) as potently as α4β2* nAChR binding (K(i) = 0.14 nM) in rat striatal sections and with ∼20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating α6β2* versus α4β2* nAChR-mediated [(3)H]dopamine release from rat striatal synaptosomes with EC(50) values of 0.007 and 0.086 μM, respectively. However, it acted as a partial agonist on α6β2* and α4β2* nAChR-mediated [(3)H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine. We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans. Varenicline again potently inhibited monkey striatal α6β2* (K(i) = 0.13 nM) and α4β2* (K(i) = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both α6β2* (EC(50) = 0.014 μM) and α4β2* (EC(50) = 0.029 μM) nAChR-mediated [(3)H]dopamine release from monkey striatal synaptosomes, again acting as a partial agonist relative to nicotine at both subtypes. These data suggest that the ability of varenicline to interact at α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid.

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Figures

Fig. 1.
Fig. 1.
Varenicline potently interacts at both α6β2* and α4β2* nAChRs in rat striatum. [125I]α-CtxMII autoradiography was used to determine the effect of varenicline on α6β2* nAChRs, while [125I]epibatidine binding in the presence of α-CtxMII was done to evaluate effects on α4β2* nAChRs (top panel). The bottom panel depicts the effect of nicotine on rat striatal α6β2* and α4β2* nAChRs for comparison. Values represent the mean ± S.E.M. of 8 rats.
Fig. 2.
Fig. 2.
Varenicline acts as a partial agonist at rat striatal α6β2* nAChRs. Top, the dose-response curve of varenicline and nicotine on total synaptosomal [3H]dopamine release from rat striatum. Middle, α6β2* nAChR-mediated release was defined as the difference in release in the absence and presence of 50 nM α-CtxMII. Bottom, α4β2* nAChR-mediated release was designated as that occurring in the presence of α-CtxMII. Both α6β2* and α4β2* varenicline-mediated maximal [3H]dopamine release were lower than that evoked by nicotine, although varenicline was more potent than nicotine. The values represent the mean ± S.E.M. of four to eight rats.
Fig. 3.
Fig. 3.
Varenicline potently competes for both α6β2* and α4β2* nAChRs in monkey striatum. [125I]α-CtxMII autoradiography was used to test the effect of varenicline on α6β2* nAChRs, while [125I]epibatidine binding in the presence of α-CtxMII was conducted to determine the effect on α4β2* nAChRs (top panel). The effects of nicotine on α6β2* and α4β2* nAChRs are shown in the bottom panel for comparison. The values represent the mean ± S.E.M. of 3 monkeys.
Fig. 4.
Fig. 4.
Varenicline is a partial agonist at monkey striatal α6β2* nAChRs. Top, the dose-response curve of varenicline and nicotine on total [3H]dopamine release from monkey striatum. Middle and bottom, α4β2* nAChR-mediated release (bottom) was designated as that occurring in the presence of 50 nM α-CtxMII, with α6β2* nAChR-mediated release defined as the difference in release in the absence and presence of α-CtxMII (middle). Both maximal α6β2* and α4β2* varenicline-stimulated [3H]dopamine release were less than that evoked by nicotine, although varenicline seemed to act more potently at both subtypes than nicotine. The values represent the mean ± S.E.M. of three monkeys.
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References

    1. Anderson DJ, Malysz J, Grønlien JH, El Kouhen R, Håkerud M, Wetterstrand C, Briggs CA, Gopalakrishnan M. (2009) Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity α4β2 subunit combination. Biochem Pharmacol 78:844–851 - PubMed
    1. Artymyshyn R, Smith A, Wolfe BB. (1990) The use of 3H standards in 125I autoradiography. J Neurosci Methods 32:185–192 - PubMed
    1. Barik J, Wonnacott S. (2009) Molecular and cellular mechanisms of action of nicotine in the CNS. Handb Exp Pharmacol 192:173–207 - PubMed
    1. Benowitz NL. (2010) Nicotine addiction. N Engl J Med 362:2295–2303 - PMC - PubMed
    1. Biala G, Staniak N, Budzynska B. (2010) Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats. Naunyn Schmiedebergs Arch Pharmacol 381:361–370 - PubMed

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