Retrograde inhibition by a specific subset of interpeduncular α5 nicotinic neurons regulates nicotine preference

Jessica L. Ables, Andreas Görlich, Beatriz Antolin-Fontes, Cuidong Wang, Sylvia M. Lipford, Michael H. Riad, Jing Ren, Fei Hu, Minmin Luo, Paul J. Kenny, Nathaniel Heintz, Ines Ibañez-Tallon

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Repeated exposure to drugs of abuse can produce adaptive changes that lead to the establishment of dependence. It has been shown that allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk of tobacco dependence. In the brain, α5-containing nAChRs are expressed at very high levels in the interpeduncular nucleus (IPN). Here we identified two nonoverlapping α5+ cell populations (α5-Amigo1 and α5-Epyc) in mouse IPN that respond differentially to nicotine. Chronic nicotine treatment altered the translational profile of more than 1,000 genes in α5-Amigo1 neurons, including neuronal nitric oxide synthase (Nos1) and somatostatin (Sst). In contrast, expression of few genes was altered in the α5-Epyc population. We show that both nitric oxide and SST suppress optically evoked neurotransmitter release from the terminals of habenular (Hb) neurons in IPN. Moreover, in vivo silencing of neurotransmitter release from the α5-Amigo1 but not from the α5-Epyc population eliminates nicotine reward, measured using place preference. This loss of nicotine reward was mimicked by shRNA-mediated knockdown of Nos1 in the IPN. These findings reveal a proaddiction adaptive response to chronic nicotine in which nitric oxide and SST are released by a specific α5+ neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine.

Original languageEnglish
Pages (from-to)13012-13017
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - 5 Dec 2017


  • Interpeduncular nucleus
  • Nicotine
  • Retrograde
  • α5 nicotinic


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