title: Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal.
abstract: Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that <10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective α4β2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxiety-related behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Turner
authors.forename: Derek S
authors.initials: DS
authors.lastname: Wilkinson
authors.forename: Rachel Lf
authors.initials: RL
authors.lastname: Poole
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Carlson
authors.forename: Julie A
authors.initials: JA
authors.lastname: Blendy
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism; D016540:Smoking Cessation / Q000379:methods; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy; D015854:Up-Regulation; D000068580:Varenicline
chemical_list: D001384:Azetidines; D001552:Benzazepines; D018722:Nicotinic Agonists; D011725:Pyridines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C514816:sazetidine-A; D009538:Nicotine; D000068580:Varenicline