Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.
Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation 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 up-regulate 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.
Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3900 Reservoir Road, NW, Washington, DC 20057, USA.
G Patrick
GP
Hussmann
Jill R
JR
Turner
Ermelinda
E
Lomazzo
Rashmi
R
Venkatesh
Vanessa
V
Cousins
Yingxian
Y
Xiao
Robert P
RP
Yasuda
Barry B
BB
Wolfe
David C
DC
Perry
Amir H
AH
Rezvani
Edward D
ED
Levin
Julie A
JA
Blendy
Kenneth J
KJ
Kellar
D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D001665:Binding Sites; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D011247:Pregnancy; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012646:Self Administration; D015854:Up-Regulation / Q000187:drug effects; D000068580:Varenicline
D001384:Azetidines; D001552:Benzazepines; D018722:Nicotinic Agonists; D011725:Pyridines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C514816:sazetidine-A; D009538:Nicotine; D000068580:Varenicline