Search

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 24mg/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 binding 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Highlights: [•] Nicotine withdrawal impaired learning. [•] Nicotine challenge enhanced learning. [•] The greatest sensitivity to nicotine challenge was observed in nicotine-withdrawn mice. [ABSTRACT FROM AUTHOR]

Abstract: Current smoking cessation aids are relatively ineffective at maintaining abstinence during withdrawal. Nicotine withdrawal is associated with a variety of symptoms including cognitive deficits and targeting these deficits may be a useful strategy for maintaining abstinence. Galantamine is an acetylcholinesterase inhibitor and allosteric modulator of nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing effects that may alleviate cognitive deficits associated with nicotine withdrawal. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice were examined. An initial acute dose–response experiment revealed that 0.5 and 1mg/kg galantamine had no effect on fear conditioning. To determine if galantamine would reverse nicotine withdrawal-related deficits in contextual fear conditioning, mice were implanted with osmotic mini-pumps that delivered chronic saline or 6.3mg/kg/d nicotine for 12 days and then pumps were removed. Training and testing of fear conditioning occurred 24 and 48h later, respectively. Nicotine withdrawal disrupted contextual fear conditioning, which was reversed with 1 but not 0.5mg/kg galantamine. Across all conditions in both studies 2mg/kg galantamine led to high levels of freezing that were likely due to nonspecific effects. The ability of galantamine to reverse nicotine withdrawal-deficits in contextual conditioning is likely mediated through enhanced levels of acetylcholine via inhibition of acetylcholinesterase, potentiation of hippocampal α4β2* nAChRs, or both. The present study suggests that acetylcholinesterase inhibitors and/or drugs that act as allosteric modulators of nAChRs might be targets for smoking cessation aids because they may alleviate withdrawal symptoms such as cognitive deficits that can lead to relapse. [Copyright &y& Elsevier]