Chrna5-Expressing Neurons in the Interpeduncular Nucleus Mediate Aversion Primed by Prior Stimulation or Nicotine Exposure

Abstract

CHRNA5/A3/B4 gene locus encoding the 5, 3, and 4 nicotinic receptor subunits. The 5 receptor has been specifically implicated because smoking-associated haplotypes contain a coding variant in the CHRNA5 gene. The Chrna5/a3/b4 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 Chrna5 mRNA expression in rodents, electrophysiological responses to nicotinic acetylcholine receptor stimulation are markedly reduced in 5-null mice. IP neurons differ markedly from their upstream ventral medial habenula cholinergic partners, which appear unaltered by loss of 5. To probe the functional role of 5-containing IP neurons, we used BAC recombineering to generate transgenic mice expressing Cre-recombinase from the Chrna5 locus. Reporter expression driven by Chrna5 Cre demonstrates that transcription of Chrna5 is regulated independently from the Chrna3/b4 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, after 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.