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Chrna5 -expressing neurons in the interpeduncular nucleus mediate aversion primed by prior stimulation or nicotine exposure
Ist Teil von
The Journal of neuroscience, 2018-08, Vol.38 (31), p.6900-6920
Ort / Verlag
United States: Society for Neuroscience
Erscheinungsjahr
2018
Quelle
EZB-FREE-00999 freely available EZB journals
Beschreibungen/Notizen
Genetic studies have shown an association between smoking and variation at the
gene locus, encoding the α5, α3 and β4 nicotinic receptor subunits. The α5 receptor has been specifically implicated because smoking-associated haplotypes contain a coding variant in the
gene. The
locus is conserved in rodents, and the restricted expression of these subunits suggests neural pathways through which the reinforcing and aversive properties of nicotine may be mediated. Here we show that in the interpeduncular nucleus (IP), the site of the highest
mRNA expression in rodents, electrophysiological responses to nicotinic acetylcholine receptor stimulation are markedly reduced in α5 null mice. In this regard, we find IP neurons differ markedly from their upstream ventral medial habenula cholinergic partners, which appear unaltered by loss of α5. To probe the functional role of α5-containing IP neurons, we used BAC recombineering to generate transgenic mice expressing Cre-recombinase from the
locus. Reporter expression driven by Chrna5
demonstrates that transcription of
is regulated independently from the
genes, transcribed on the opposite strand. Chrna5-expressing IP neurons are GABAergic and project to distant targets in the mesopontine raphe and tegmentum, rather than forming local circuits. Optogenetic stimulation of Chrna5-expressing IP neurons failed to elicit physical manifestations of withdrawal. However, following recent prior stimulation or exposure to nicotine, IP stimulation becomes aversive. These results using mice of both sexes support the idea that the risk allele of CHRNA5 may increase the drive to smoke via loss of IP-mediated nicotine aversion.
Understanding the receptors and neural pathways underlying the reinforcing and aversive effects of nicotine may suggest new treatments for tobacco addiction. Part of the individual variability in smoking is associated with specific forms of the α5 nicotinic receptor subunit gene. Here we show that deletion of the α5 subunit in mice markedly reduces the cellular response to nicotine and acetylcholine in the interpeduncular nucleus (IP). Stimulation of α5-expressing IP neurons using optogenetics is aversive, but this effect requires priming by recent prior stimulation or exposure to nicotine.. These results support the idea that the smoking-associated variant of the α5 gene may increase the drive to smoke via loss of IP-mediated nicotine aversion.