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

Abstract

Although 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, Groton, CT ); 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. It is noteworthy that the selective partial agonists for a4b2, ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine], and a7, ABT-107North Chicago, IL), 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 short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and b2-containing nAChRs were measured using [3 H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotinedependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

“…In contrast, an anxiogenic effect of withdrawal at 24 hours is observed as an increased latency to consume a palatable food in a novel environment when compared to nicotine-treated mice. [28][29][30][31]58 The increased time observed in the BDNF Met/Met mice to initially approach and eat the palatable food during training for the NIH test ( Figure 1B) might be indicative of either increased anxietylike behavior as the food is a novel object introduced into the home cage, or it could be revealing a deficit in training behavior as studies have shown that the BDNF Met/Met mice exhibit impaired spatial and working memory. 59 However, no significant differences between genotype or between treatment groups by the end of training were observed, suggesting that although acquisition of the task was slow, it did not affect the overall performance of these mice on home or novel day.…”

“…[28][29][30] In particular, studies have shown an anxiolytic effect of chronic nicotine as measured by a decreased latency to consume a palatable food in a novel environment when compared to saline-treated mice. In contrast, an anxiogenic effect of withdrawal at 24 hours is observed as an increased latency to consume a palatable food in a novel environment when compared to nicotine-treated mice.…”

“…The NIH test was conducted as previously described [29][30] with mice housed in groups of two. Mice were placed in a testing room with dividers separating their home cage, and allowed to acclimate for 1 hour prior to presentation of a palatable food (peanut butter chips; Nestle, Glendale, CA).…”

Nicotine Addiction and Psychiatric Disorders

“…As in the effects of nicotine on fear conditioning, there is evidence that β2-containing nAChRs mediate nicotine’s effects on anxiety. For example, an α4β2 nAChR agonist, ABT-418, was found to increase open arm time in the EPM and both ABT-418 and an α4β2 nAChR partial agonist, ABT-089, reversed the anxiogenic effects of nicotine withdrawal (Brioni et al, 1994; Decker et al, 1994; Yohn, Turner, & Blendy, 2014). Brioni et al (1994) also showed that the anxiolytic effects of ABT-418 were reversed by the nAChR antagonist mecamylamine, which suggests that sustained nAChR activity is required for the anxiolytic effect of ABT-418.…”

“…Also, Paylor et al (1998) showed that α7 nAChR-lacking KO mice show decreased levels of anxiety in the EPM paradigm, while an α7-selective agonist, PNU-282987, was shown to increase anxiety in the OF paradigm (Pandya & Yakel, 2013). Similarly, desensitization of α7 nAChRs by using an α7 partial agonist, ABT-107, was found to reverse the anxiogenic effects of nicotine withdrawal (Yohn et al, 2014). Overall, these results suggest that in animals, nicotine has differential effects on anxiety in different strains/species and anxiety-related animal models.…”