Activation of α4β2*/α 6β2* Nicotinic Receptors Alleviates Anxiety During Nicotine Withdrawal Without Upregulating Nicotinic Receptors.

Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 03/2014; 349(2). DOI: 10.1124/jpet.113.211706
Source: PubMed

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.

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