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 o10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective a4b2 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 anxietyrelated 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.

Activation ofα4β2*/α6β2* Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors

“…For example, in naive animals, shortterm and long-term varenicline administration is anxiolytic in the NIH test (Turner et al, 2010). However, in nicotineexperienced animals, short-term administration of varenicline during nicotine withdrawal fails to alleviate anxiety-like behavior (Turner et al, 2013b), suggesting a differential effect of varenicline based on the drug experienced state of the subject. Additionally, a recent study in smokers identified anxiety as one of the symptom domains in which varenicline treatment was ineffective (Cinciripini et al, 2013).…”

“…The NIH paradigm is a sensitive measure for potential anxiolytic drugs and anxiogenic effects of withdrawal on both acute and extended drug administration paradigms (Dulawa et al, 2004;Dulawa and Hen, 2005). The NIH test is sensitive to the anxiolytic effect of long-term nicotine (Turner et al, 2010(Turner et al, , 2013b and the anxiogenic effect of 24-hour withdrawal from nicotine (as shown in Fig. 1).…”

“…Long-term exposure to varenicline upregulates nAChRs, which parallels its anxiolytic effects during cessation from nicotine (Turner et al, 2011). However, the more selective a4b2 nAChR compound, sazetidine-A, does not increase nAChRs despite behavioral anxiolytic effects (Turner et al, 2010(Turner et al, , 2013bHussmann et al, 2012). Therefore, the role of nAChR upregulation in mediating withdrawal-induced anxiety is as yet unclear.…”

“…Varenicline (Chantix; Pfizer, Groton, CT), a partial agonist at a4b2 nicotinic acetylcholine receptors (nAChRs) and a full agonist at a7 and a3b4 nAChRs is currently the best in class treatment of smoking cessation (Coe et al, 2005;Garrison and Dugan, 2009). However, although varenicline has been shown to improve both concentration and depressed mood and mitigate craving, recent studies in mice and human subjects have shown treatment does not improve nicotine withdrawal-induced anxiety (Turner et al, 2013b;Cinciripini et al, 2013). This may be of special importance because anxiety arising due to nicotine withdrawal has been correlated with relapse rates (Zhou et al, 2009).…”

Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice

“…Pumps were filled with 100μL of either sterile saline or nicotine hydrogen tartrate (Sigma Co, St. Louis, MO) dissolved in saline, and implanted subcutaneously in isoflurane-anesthetized mice under aseptic surgical conditions. Nicotine was administered at a dose of 18mg/kg/day (reported as free base) previously reported to desensitize nAChRs (Turner et al 2010; Turner et al 2013; Wilkinson et al, 2013) and produce reversal learning deficits in mice (Ortega et al 2013). …”