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

TitleVTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation.
Publication TypeJournal Article
Year of Publication2014
AuthorsGrieder TE, Herman MA, Contet C, Tan LA, Vargas-Perez H, Cohen A, Chwalek M, Maal-Bared G, Freiling J, Schlosburg JE, Clarke L, Crawford E, Koebel P, Repunte-Canonigo V, Sanna PP, Tapper AR, Roberto M, Kieffer BL, Sawchenko PE, Koob GF, van der Kooy D, George O
JournalNat Neurosci
Volume17
Issue12
Pagination1751-8
Date Published2014 Dec
ISSN1546-1726
KeywordsAnimals, Corticotropin-Releasing Hormone, Humans, Inhibitory Postsynaptic Potentials, Male, Mice, Mice, Inbred C57BL, Neurons, Nicotine, Organ Culture Techniques, Rats, Rats, Wistar, Substance Withdrawal Syndrome, Ventral Tegmental Area
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.

DOI10.1038/nn.3872
Alternate JournalNat. Neurosci.
PubMed ID25402857
PubMed Central IDPMC4241147
Grant ListAA006420 / AA / NIAAA NIH HHS / United States
AA013498 / AA / NIAAA NIH HHS / United States
AA015566 / AA / NIAAA NIH HHS / United States
AA016658 / AA / NIAAA NIH HHS / United States
AA021491 / AA / NIAAA NIH HHS / United States
AA021667 / AA / NIAAA NIH HHS / United States
DA023597 / DA / NIDA NIH HHS / United States
DA031566 / DA / NIDA NIH HHS / United States
DA035371 / DA / NIDA NIH HHS / United States
DK026741 / DK / NIDDK NIH HHS / United States
F32 AA020430 / AA / NIAAA NIH HHS / United States
P60 AA006420 / AA / NIAAA NIH HHS / United States
R01 AA021491 / AA / NIAAA NIH HHS / United States
R01 AA021667 / AA / NIAAA NIH HHS / United States
R01 DA023597 / DA / NIDA NIH HHS / United States
R01 DA031566 / DA / NIDA NIH HHS / United States
R01 DA035371 / DA / NIDA NIH HHS / United States
T32 AA007456 / AA / NIAAA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada