VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation.
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.
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Taryn E
TE
Grieder
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Melissa A
MA
Herman
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Candice
C
Contet
The Salk Institute, La Jolla, California, USA.
Laura A
LA
Tan
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Hector
H
Vargas-Perez
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Ami
A
Cohen
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Michal
M
Chwalek
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Geith
G
Maal-Bared
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
John
J
Freiling
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Joel E
JE
Schlosburg
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Laura
L
Clarke
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Elena
E
Crawford
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / Université de Strasbourg, Illkirch, France.
Pascale
P
Koebel
Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
Vez
V
Repunte-Canonigo
Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
Pietro P
PP
Sanna
Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Andrew R
AR
Tapper
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Marisa
M
Roberto
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.
Brigitte L
BL
Kieffer
The Salk Institute, La Jolla, California, USA.
Paul E
PE
Sawchenko
National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, USA.
George F
GF
Koob
Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Derek
D
van der Kooy
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Olivier
0000000237005003
O
George
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000009:adverse effects*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
D009538:Nicotine; D003346:Corticotropin-Releasing Hormone