Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal.
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.
SourceAvailable from: Vinay V Parikh[Show abstract] [Hide abstract]
ABSTRACT: Rationale Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. Objectives In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2 subunit-containing nAChR gene (β2+/− or β2−/−) performing an operant cognitive flexibility task. Results Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2−/− mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/− mice. Conclusions Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies.Psychopharmacology 10/2014; 232(7). DOI:10.1007/s00213-014-3754-4 · 3.99 Impact Factor
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ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this perspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this article analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This perspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.Journal of Medicinal Chemistry 06/2014; 57(20). DOI:10.1021/jm401937a · 5.48 Impact Factor
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ABSTRACT: What is known and objectiveTobacco smoking remains a major health problem. Nicotine binds to nicotinic acetylcholine receptors (nAChRs), which can cause addiction and withdrawal symptoms upon cessation of nicotine administration. Pharmacotherapies for nicotine addiction target brain alterations that underlie withdrawal symptoms. This review will delineate the involvement of the β2 subunit of neuronal nAChRs in nicotine reward and in generating withdrawal symptoms to better understand the efficacy of smoking cessation pharmacotherapies.CommentChronic nicotine desensitizes and upregulates β2 subunit-containing nAChRs, and the prolonged upregulation of receptors may underlie symptoms of withdrawal. Experimental research has demonstrated that the β2 subunit of neuronal nAChRs is necessary for generating nicotine reward and withdrawal symptoms.What is new and conclusionSmoking cessation pharmacotherapies act on β2 subunit-containing nAChRs to reduce nicotine reward and withdrawal symptom severity.Journal of Clinical Pharmacy and Therapeutics 05/2014; DOI:10.1111/jcpt.12171 · 1.53 Impact Factor