Journal
PSYCHOPHARMACOLOGY
Volume 229, Issue 3, Pages 503-513Publisher
SPRINGER
DOI: 10.1007/s00213-013-3235-1
Keywords
CHRNA5; alpha 5 nicotinic receptors; Nicotine; Reward; Aversion; Habenula; Interpeduncular nucleus; Conditioned taste aversion
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Funding
- National Institute on Drug Abuse [D032543, DA020686]
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Allelic variation in the alpha 5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of alpha 5* nAChRs in the effects of nicotine on brain reward systems. 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 alpha 5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion procedure. Lower nicotine doses (0.03125-0.125 mg/kg) decreased ICSS thresholds in wild-type and alpha 5 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 alpha 5 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 alpha 5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated alpha 5 knockout mice. alpha 5* 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, alpha 5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of alpha 5* 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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