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.
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ABSTRACT: Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole-genome sequencing) to identify cAMP response element-binding protein (CREB) targets following chronic nicotine administration and withdrawal (WD) in rodents. We found that chronic nicotine and WD differentially modulate CREB binding to the gene for neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine and nicotine WD in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following WD from chronic nicotine treatment. To translate these data for human relevance, single-nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support the association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the epidermal growth factor family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also upregulated following nicotine treatment and WD. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine WD compared with control animals, suggesting a role for NRG3 in nicotine dependence. Although the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.Molecular Psychiatry advance online publication, 3 September 2013; doi:10.1038/mp.2013.104.Molecular Psychiatry 09/2013; 19(7). DOI:10.1038/mp.2013.104 · 14.50 Impact Factor
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ABSTRACT: While nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist Varenicline (Chantix; Pfizer), however treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. Interestingly, the selective partial agonists for α4β2, ABT-089, and α7, ABT-107, (AbbVie) have not been evaluated as possible therapeutics for nicotine cessation. Therefore we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that acute ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while chronic ABT-089 but not chronic ABT-107 reduces anxiety-like behavior during withdrawal. Following behavioral testing, brains were harvested and beta2-containing nAChRs were measured using [3H]Epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed following nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotine-dependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.Journal of Pharmacology and Experimental Therapeutics 03/2014; 349(2). DOI:10.1124/jpet.113.211706 · 3.97 Impact Factor
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ABSTRACT: Nicotine addiction is associated with the development of tolerance and the emergence of withdrawal symptoms upon cessation of chronic nicotine administration. Changes in cognition, including deficits in learning, are one of the most common withdrawal symptoms reported by smokers. However, the neural substrates of tolerance to the effects of nicotine on learning and the substrates of withdrawal deficits in learning are unknown, and in fact it is unclear whether a common mechanism is involved in both. The present study tested the hypothesis that tolerance and withdrawal are separate processes and that nicotinic acetylcholine receptor (nAChR) upregulation underlies changes in learning associated with withdrawal but not tolerance. C57BL/6 male mice were administered a dose of nicotine (3, 6.3, 12, or 24 mg/kg/d) chronically for varying days and tested for the onset of tolerance to the effects of nicotine on learning. Follow up experiments examined the number of days of chronic nicotine treatment required to produce withdrawal deficits in learning and a significant increase in [3H]epibatidine in the hippocampus indicative of receptor upregulation. The results indicate that tolerance onset was influenced by dose of chronic nicotine, that tolerance occurred before withdrawal deficits in learning emerged, and that nAChR upregulation in the dorsal hippocampus was associated with withdrawal but not tolerance. This suggests that for the effects of nicotine on learning, tolerance and withdrawal involve different substrates. These findings are discussed in terms of implications for development of therapeutics that target symptoms of nicotine addiction and for theories of addiction.Brain research 04/2014; 1559. DOI:10.1016/j.brainres.2014.02.038 · 2.84 Impact Factor