Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomeriza...

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Bibliographic Details
Published in:The Journal of neuroscience 2015-04
Main Authors: Navarro Brugal, Gemma, Quiroz, César, Moreno-Delgado, David, Sierakowiak, Adam, McDowell, Kimberly, Moreno Guillén, Estefanía, Rea, William, Cai, Ning-Sheng, Aguinaga Andrés, David, Howell, Lesley A, Hausch, Felix, Cortés Tejedor, Antonio, Mallol Montero, Josefa, Casadó, Vicent, Lluís i Biset, Carme, Canela Campos, Enric I, Ferré, Sergi, McCormick, Peter J
Format: Article
Language:English
Subjects:
Cell receptors
Cocaine
Cocaïna
Receptors cel·lulars
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Summary:Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target sigma1 receptor (sigma1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking.
ISSN:0270-6474