Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum

Nat Commun. 2018 Jul 13;9(1):2710. doi: 10.1038/s41467-018-04654-2.


Nicotine use can lead to dependence through complex processes that are regulated by both its rewarding and aversive effects. Recent studies show that aversive nicotine doses activate excitatory inputs to the interpeduncular nucleus (IPN) from the medial habenula (MHb), but the downstream targets of the IPN that mediate aversion are unknown. Here we show that IPN projections to the laterodorsal tegmentum (LDTg) are GABAergic using optogenetics in tissue slices from mouse brain. Selective stimulation of these IPN axon terminals in LDTg in vivo elicits avoidance behavior, suggesting that these projections contribute to aversion. Nicotine modulates these synapses in a concentration-dependent manner, with strong enhancement only seen at higher concentrations that elicit aversive responses in behavioral tests. Optogenetic inhibition of the IPN-LDTg connection blocks nicotine conditioned place aversion, suggesting that the IPN-LDTg connection is a critical part of the circuitry that mediates the aversive effects of nicotine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Avoidance Learning / physiology*
  • Channelrhodopsins / genetics
  • Channelrhodopsins / metabolism
  • Electrodes, Implanted
  • GABAergic Neurons / cytology
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • Gene Expression
  • Habenula / cytology
  • Habenula / drug effects*
  • Habenula / metabolism
  • Interpeduncular Nucleus / cytology
  • Interpeduncular Nucleus / drug effects*
  • Interpeduncular Nucleus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Nicotine / pharmacology*
  • Optogenetics
  • Reward
  • Stereotaxic Techniques
  • Synapses / drug effects
  • Synapses / physiology
  • Tegmentum Mesencephali / cytology
  • Tegmentum Mesencephali / drug effects*
  • Tegmentum Mesencephali / metabolism
  • Transgenes


  • Channelrhodopsins
  • Nicotine