ArticleThe Journal of pharmacology and experimental therapeutics2012
Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.
Article in The Journal of pharmacology and experimental therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 34 citations in OpenAlex.
- A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco-deprived and -satiated smokers.Human psychopharmacology · 2018Trial
- Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A.Addiction biology · 2021Article
- Determining the pharmacokinetics of nicotinic drugs in the endoplasmic reticulum using biosensors.The Journal of general physiology · 2019Article
- Oral sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, reduces nicotine self-administration in rats.Pharmacology, biochemistry, and behavior · 2019Article
- Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation.eLife · 2017Article
- Chronic treatment with varenicline changes expression of four nAChR binding sites in mice.Neuropharmacology · 2015Article
- Sazetidine-A Activates and Desensitizes Native α7 Nicotinic Acetylcholine Receptors.Neurochemical research · 2015Article
- Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors.Molecular pharmacology · 2015Article
- Orthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation.Frontiers in molecular neuroscience · 2015Review
- Administration of the nicotinic acetylcholine receptor agonists ABT-089 and ABT-107 attenuates the reinstatement of nicotine-seeking behavior in rats.Behavioural brain research · 2014Article
- Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.Journal of medicinal chemistry · 2014Review
- Role for the nicotinic cholinergic system in movement disorders; therapeutic implications.Pharmacology & therapeutics · 2014Review
- Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal.Expert opinion on drug discovery · 2014Review
- Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors.The Journal of pharmacology and experimental therapeutics · 2014Article
- Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain.Journal of neurochemistry · 2014Article
- Dissociation of tolerance and nicotine withdrawal-associated deficits in contextual fear.Brain research · 2014Article
- Effectiveness of nicotinic agonists as desensitizers at presynaptic α4β2- and α4α5β2-nicotinic acetylcholine receptors.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2014Article
- Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Article
- Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2013Article
- α4β2 Nicotinic receptors play a role in the nAChR-mediated decline in L-dopa-induced dyskinesias in parkinsonian rats.Neuropharmacology · 2013Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.