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Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice

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Abstract

Objective

Allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of α5* nAChRs in the effects of nicotine on brain reward systems.

Materials and methods

Effects of acute (0.03125–0.5 mg/kg SC) or chronic (24 mg/kg per day; osmotic minipump) nicotine and mecamylamine-precipitated withdrawal on intracranial self-stimulation (ICSS) thresholds were assessed in wild-type and α5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion procedure.

Results

Lower nicotine doses (0.03125–0.125 mg/kg) decreased ICSS thresholds in wild-type and α5 knockout mice. At higher doses (0.25–0.5 mg/kg), threshold-lowering effects of nicotine were diminished in wild-type mice, whereas nicotine lowered thresholds across all doses tested in α5 knockout mice. Nicotine (1.5 mg/kg) conditioned a taste aversion to saccharine equally in both genotypes. Mecamylamine (5 mg/kg) elevated ICSS thresholds by a similar magnitude in wild-type and α5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated α5 knockout mice.

Conclusion

α5* nAChRs are not involved in reward-enhancing effects of lower nicotine doses, the reward-inhibiting effects of nicotine withdrawal, or the general noxious effects of higher nicotine doses. Instead, α5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of α5* nAChR signaling greatly expands the range of nicotine doses that facilitate brain reward activity, which may help explain the increased tobacco addiction vulnerability associated with CHRNA5 risk alleles.

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Acknowledgments

This work was supported by a grant from the National Institute on Drug Abuse (D032543 to C.D.F. and DA020686 to P.J.K.). This is manuscript number 23093 from The Scripps Research Institute.

Conflict of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute–Florida, 130 Scripps Way, Jupiter, FL, 33458, USA

    Christie D. Fowler, Luis Tuesta & Paul J. Kenny

  2. Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA

    Paul J. Kenny

  3. Kellogg School of Science and Technology, The Scripps Research Institute–Florida, Jupiter, FL, 33458, USA

    Christie D. Fowler, Luis Tuesta & Paul J. Kenny

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  1. Christie D. Fowler
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Correspondence to Paul J. Kenny.

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Fowler, C.D., Tuesta, L. & Kenny, P.J. Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice. Psychopharmacology 229, 503–513 (2013). https://doi.org/10.1007/s00213-013-3235-1

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