VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation

Nat Neurosci. 2014 Dec;17(12):1751-8. doi: 10.1038/nn.3872. Epub 2014 Nov 17.


Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corticotropin-Releasing Hormone / physiology*
  • Humans
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nicotine / adverse effects*
  • Organ Culture Techniques
  • Rats
  • Rats, Wistar
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / psychology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*


  • Nicotine
  • Corticotropin-Releasing Hormone