Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

Trends Pharmacol Sci. 2017 Feb;38(2):169-180. doi: 10.1016/ Epub 2016 Nov 24.


While innovative modern neuroscience approaches have aided in discerning brain circuitry underlying negative emotional behaviors including fear and anxiety responses, how these circuits are recruited in normal and pathological conditions remains poorly understood. Recently, genetic tools that selectively manipulate single neuronal populations have uncovered an understudied circuit, the medial habenula (mHb)-interpeduncular (IPN) axis, that modulates basal negative emotional responses. Interestingly, the mHb-IPN pathway also represents an essential circuit that signals heightened anxiety induced by nicotine withdrawal. Insights into how this circuit interconnects with regions more classically associated with anxiety, and how chronic nicotine exposure induces neuroadaptations resulting in an anxiogenic state, may thereby provide novel strategies and molecular targets for therapies that facilitate smoking cessation, as well as for anxiety relief.

Keywords: anxiety; fear; interpeduncular nucleus; medial habenula; nicotine withdrawal.

Publication types

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

MeSH terms

  • Animals
  • Anxiety Disorders / drug therapy
  • Anxiety Disorders / etiology*
  • Corticotropin-Releasing Hormone / physiology
  • Emotions
  • Habenula / physiology*
  • Humans
  • Interpeduncular Nucleus / physiology*
  • Mice
  • Receptors, Nicotinic / physiology
  • Tobacco Use Disorder / drug therapy
  • Tobacco Use Disorder / etiology*
  • Ventral Tegmental Area / physiology


  • Receptors, Nicotinic
  • Corticotropin-Releasing Hormone