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

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

Author information

1
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
2
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
3
The Salk Institute, La Jolla, California, USA.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / Université de Strasbourg, Illkirch, France.
5
Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
6
Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
7
1] Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / Université de Strasbourg, Illkirch, France. [2] Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
8
National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, USA.

Abstract

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.

PMID:
25402857
PMCID:
PMC4241147
DOI:
10.1038/nn.3872
[Indexed for MEDLINE]
Free PMC Article

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