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Discriminative-stimulus effects of NS9283, a nicotinic α4β2* positive allosteric modulator, in nicotine-discriminating rats

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Abstract

Rationale

Neuronal α4β2* nicotinic acetylcholine receptors mediate cognition, pain, and the discriminative and reinforcing effects of nicotine. In addition to traditional orthosteric agonists, α4β2* positive allosteric modulators (PAMs) have recently been identified. With increased subtype selectivity relative to agonists, PAMs administered alone or in combination with low-dose α4β2* agonists may be used as powerful tools for increasing our understanding of α4β2* pharmacology.

Objectives

The present experiments tested the nicotine discriminative-stimulus effects of the α4β2* PAM NS9283 (A-969933) in the presence and absence of low-dose nicotine or nicotinic subtype-selective agonist.

Methods

Rats were trained to discriminate 0.4 mg/kg nicotine from saline in a two-lever drug discrimination paradigm. In subsequent generalization tests, rats were administered nicotine, the α4β2*-preferring agonist ABT-594, and NS9283, alone or in two-drug combinations.

Results

Nicotine and ABT-594 showed dose-dependent nicotine generalization. NS9283 alone resulted in a non-significant increase in nicotine-appropriate lever selection. Combination of non-effective doses of nicotine or ABT-594 with escalating doses of NS9283 resulted in a complete conversion to 100 % nicotine-appropriate choice in the case of nicotine combination and incomplete, though significant, generalization for ABT-594.

Conclusions

The α4β2* PAM NS9283 alone did not produce nicotine-like discriminative effects, but did demonstrate dose-related increases in nicotine lever choice when combined with a non-effective dose of nicotine or the α4β2* agonist ABT-594. This finding provides confirmation of the positive allosteric modulating effect of NS9283 in a functional in vivo paradigm. NS9283 is a potentially valuable tool for studying the role of α4β2* receptors in various nicotinic acetylcholine receptor-related functions.

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Abbreviations

PAM:

Positive allosteric modulator

nAChR:

Nicotinic acetylcholine receptor

FR10:

Fixed ratio 10

ED50 :

Median effective dose

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Acknowledgments

Animals were treated in accordance with guidelines established by the AbbVie Animal Care and Use Committee and National Institutes of Health Guide for The Care and Use of Laboratory Animals in an AAALAC-accredited facility.

This study was sponsored by AbbVie, Inc. AbbVie contributed to the study design, research, interpretation of data, writing, reviewing, and approval of the manuscript. All authors are current or past employees of AbbVie.

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  1. Neuroscience Drug Discovery, AbbVie, 1 N. Waukegan Rd., Bldg AP-9A, North Chicago, IL, 60064-6125, USA

    Eric G. Mohler, Stanley R. Franklin & Lynne E. Rueter

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  1. Eric G. Mohler
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  2. Stanley R. Franklin
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  3. Lynne E. Rueter
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Correspondence to Eric G. Mohler.

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Mohler, E.G., Franklin, S.R. & Rueter, L.E. Discriminative-stimulus effects of NS9283, a nicotinic α4β2* positive allosteric modulator, in nicotine-discriminating rats. Psychopharmacology 231, 67–74 (2014). https://doi.org/10.1007/s00213-013-3207-5

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  • DOI: https://doi.org/10.1007/s00213-013-3207-5

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