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

Navarro, Gemma, Quiroz, César, Moreno-Delgado, David, Sierakowiak, Adam, McDowell, Kimberly, Moreno, Estefanía, Rea, William, Cai, Ning-Sheng, Aguinaga, David, Howell, Lesley A., Hausch, Felix, Cortés, Antonio, Mallol, Josefa, Casadó, Vicent, Lluís, Carme, Canela, Enric I., Ferré, Sergi and McCormick, Peter J. (2015) Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. The Journal of Neuroscience, 35 (17). pp. 6639-6653. ISSN 1529-2401

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Abstract

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 σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–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.

Item Type:	Article
Additional Information:	Articles are released under a Creative Commons Attribution License after a 6 months embargo
Uncontrolled Keywords:	cocaine,crf receptor,gpcr heteromer,orexin receptor,sigma receptor
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Depositing User:	Pure Connector
Date Deposited:	19 Nov 2015 15:04
Last Modified:	20 Oct 2022 22:36
URI:	https://ueaeprints.uea.ac.uk/id/eprint/55486
DOI:	10.1523/JNEUROSCI.4364-14.2015

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