Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal

Nat Commun. 2015 Apr 21:6:6770. doi: 10.1038/ncomms7770.

Abstract

Increased anxiety is a prominent withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear. Here we show that withdrawal-induced anxiety increases activity of neurons in the interpeduncular intermediate (IPI), a subregion of the interpeduncular nucleus (IPN). IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signalling, which modulated glutamatergic input from the medial habenula (MHb). Pharmacological blockade of IPN CRF1 receptors or optogenetic silencing of MHb input reduced IPI activation and alleviated withdrawal-induced anxiety; whereas IPN CRF infusion in mice increased anxiety. We identified a mesointerpeduncular circuit, consisting of ventral tegmental area (VTA) dopaminergic neurons projecting to the IPN, as a potential source of CRF. Knockdown of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal. These data indicate that increased CRF receptor signalling within a VTA-IPN-MHb circuit triggers anxiety during nicotine withdrawal.

Publication types

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

MeSH terms

  • Animals
  • Anxiety / etiology*
  • Corticotropin-Releasing Hormone / metabolism*
  • Habenula / anatomy & histology
  • Habenula / physiology*
  • Interpeduncular Nucleus / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Net
  • Nicotine / adverse effects*
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Signal Transduction / physiology
  • Substance Withdrawal Syndrome / physiopathology
  • Ventral Tegmental Area / physiology*

Substances

  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Nicotine
  • Corticotropin-Releasing Hormone