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

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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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 αnAChRs 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: αnAChRs 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, αnAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of αnAChR 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.

Original languageEnglish (US)
Pages (from-to)503-513
Number of pages11
JournalPsychopharmacology
Volume229
Issue number3
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • α5 nicotinic receptors
  • Aversion
  • CHRNA5
  • Conditioned taste aversion
  • Habenula
  • Interpeduncular nucleus
  • Nicotine
  • Reward

ASJC Scopus subject areas

  • Pharmacology

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