Attenuation of nicotine taking and seeking in rats by the stoichiometry-selective alpha4beta2 nicotinic acetylcholine receptor positive allosteric modulator NS9283

Abstract

Rationale

The rewarding and reinforcing effects of nicotine are produced, in large part, by activation of neuronal α4β2* nicotinic acetylcholine receptors (nAChRs), pentameric protein complexes comprised of different stoichiometries of α4 and β2 subunits. However, little is known about the functional role of distinct subtypes of α4β2* nAChRs in nicotine addiction.

Objectives

NS9283 represents a new class of stoichiometry-selective positive allosteric modulators (PAMs) that selectively bind to α4β2 nAChRs containing three α4 and two β2 subunits (3(α4)2(β2) nAChRs). The present experiments were designed to determine the effects of NS9283 on nicotine self-administration and the reinstatement of nicotine-seeking behavior, an animal model of smoking relapse. Parallel studies of sucrose self-administration and reinstatement were conducted in separate cohorts of rats to determine if the effects of NS9283 generalized to other reinforced behaviors.

Results

Acute and repeated administration of NS9283 dose-dependently reduced nicotine self-administration and reinstatement in male Sprague Dawley rats. These effects were reinforcer specific as no effects of NS9283 on sucrose self-administration and reinstatement were noted. NS9283 also failed to substitute for nicotine in supporting self-administration behavior suggesting that, at the doses tested, NS9283 alone is not reinforcing.

Conclusion

Taken together, these results provide compelling evidence that stoichiometry-selective PAMs of 3(α4)2(β2) nAChRs attenuate nicotine taking and seeking in rats and suggest that targeting 3(α4)2(β2) nAChRs may represent a promising therapeutic strategy for preventing smoking relapse.

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Acknowledgements

HDS was supported in part by a K01 training grant (DA030445), an R01 (DA037897) and an R21 (DA039393) from the National Institutes of Health (NIH), a pilot grant (P50-CA-143187) from the Center for Interdisciplinary Research on Nicotine Addiction (CIRNA) at UPenn, and an Institutional Research Grant (IRG-78-002-31) from the American Cancer Society and the Abramson Cancer Center at UPenn. The authors would like to thank Aniona for generously providing NS9283 for these studies. The authors also extend a note of gratitude to Adrian Arreola and Duncan Van Nest for their technical assistance.

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Correspondence to Heath D. Schmidt.

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Authors’ contribution

HDS was responsible for the study concept and design, supervised and contributed to the acquisition of data, analyzed the data, and drafted the manuscript. JJM contributed to the acquisition of animal data, analyzed the data, and helped draft the manuscript. KS-N also provided critical revision of the manuscript for important intellectual content. All authors critically reviewed content and approved the final version for publication.

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Maurer, J.J., Sandager-Nielsen, K. & Schmidt, H.D. Attenuation of nicotine taking and seeking in rats by the stoichiometry-selective alpha4beta2 nicotinic acetylcholine receptor positive allosteric modulator NS9283. Psychopharmacology 234, 475–484 (2017). https://doi.org/10.1007/s00213-016-4475-7

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Keywords

  • Nicotine addiction
  • Relapse
  • Self-administration
  • Smoking
  • Reinstatement
  • Positive allosteric modulator
  • E-cigarette