Divergent functional effects of sazetidine-A and varenicline during nicotine withdrawal

Jill R. Turner, Derek S. Wilkinson, Rachel Lf Poole, Thomas J. Gould, Gregory C. Carlson, Julie A. Blendy

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2035-2047
Number of pages13
JournalNeuropsychopharmacology
Volume38
Issue number10
DOIs
StatePublished - Sep 2013

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

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