TY - JOUR
T1 - Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain
AU - Hussmann, G. Patrick
AU - Turner, Jill R.
AU - Lomazzo, Ermelinda
AU - Venkatesh, Rashmi
AU - Cousins, Vanessa
AU - Xiao, Yingxian
AU - Yasuda, Robert P.
AU - Wolfe, Barry B.
AU - Perry, David C.
AU - Rezvani, Amir H.
AU - Levin, Edward D.
AU - Blendy, Julie A.
AU - Kellar, Kenneth J.
PY - 2012/11
Y1 - 2012/11
N2 - Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This upregulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at α4β2*nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ∼150 times its affinity for α4β2*nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not upregulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all α4β2*nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.
AB - Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This upregulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at α4β2*nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ∼150 times its affinity for α4β2*nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not upregulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all α4β2*nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.
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U2 - 10.1124/jpet.112.198085
DO - 10.1124/jpet.112.198085
M3 - Article
C2 - 22899752
AN - SCOPUS:84867606345
SN - 0022-3565
VL - 343
SP - 441
EP - 450
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -