Article

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

Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 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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Available from: Jill R Turner, Nov 18, 2015
    • "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. "
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    • "nAChRs, reversed the anxiogenic effects of nicotine withdrawal in a novelty-induced hypophagia paradigm, an anxiety paradigm measuring the novelty-induced reduction of feeding behavior. Also in this task, Yohn et al. [252] found that a partial agonist of a4b2 nAChR, ABT-089, resulted in the reversal of withdrawal-related anxiety but produced anxiogenic effects in nicotine naïve animals. Therefore, these results show that a4b2 and a7 nAChRs differentially mediate both anxiety and nicotine's effects on anxiety. "
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    • "Consistent with their extensive CNS localization, a7 nAChRs are implicated in numerous functions including development, maintenance, survival, synaptic plasticity, neurotransmitter release and/or immune responsiveness . Their acute and long term effects on these cellular processes may modulate behaviors such as anxiety, attention, learning, memory, movement and sensory gating, with consequent implications for Alzheimer's disease, Parkinson's disease, schizophrenia, traumatic brain injury, autism, addiction, pain and immune/ inflammatory disorders30313233343536. "
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    ABSTRACT: Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently L-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces L-dopa-induced dyskinesias, a side effect of L-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that α7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for α7 nAChRs in protection against neurodegenerative effects and for the reduction of L-dopa-induced dyskinesias. Altogether, this work suggests that α7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with L-dopa therapy. Copyright © 2015. Published by Elsevier Inc.
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