Role of ?5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice.

ABSTRACT: Allelic variation in the ?5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of ?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 ?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 ?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 ?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 ?5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated ?5 knockout mice.?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, ?5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of ?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.

SUBMITTER: Fowler CD 

PROVIDER: S-EPMC3930613 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature