Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal.

Departments of Pharmacology, Philadelphia, PA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 04/2013; DOI: 10.1038/npp.2013.105
Source: PubMed

ABSTRACT Smoking is the largest preventable cause of death in the United States ADDIN EN.CITE CDC 2007 286 286 286 17 CDC Cigarette smoking among adults--United States, 2006. Morbid. Mortal. Wkly. Rep. Morbid. Mortal. Wkly. Rep. 1157-61 56 44 2007 (CDC, 2007). Furthermore, a recent study found that less than 10% of quit attempts resulted in continuous abstinence for one yearADDIN EN.CITE ADDIN EN.CITE.DATA (Gonzales et al, 2006). 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 to 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.Neuropsychopharmacology accepted article preview online, 29 April 2013; doi:10.1038/npp.2013.105.

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