Orexin-Corticotropin-Releasing Factor Receptor Heteromers in the Ventral 
Tegmental Area as Targets for Cocaine

Navarro, Gemma; Quiroz, Cesar; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefania; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortes, Antonio; Mallol, Josefa; Casado, Vicent; Lluis, Carme; Canela, Enric I.; Ferre, Sergi; McCormick, Peter J.

doi:10.1523/JNEUROSCI.4364-14.2015

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Orexin-Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

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Hausch, Felix
Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Navarro, G., Quiroz, C., Moreno-Delgado, D., Sierakowiak, A., McDowell, K., Moreno, E., et al. (2015). Orexin-Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine. JOURNAL OF NEUROSCIENCE, 35(17), 6639-6653. doi:10.1523/JNEUROSCI.4364-14.2015.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-8CAE-C

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 sigma(1) receptor (sigma R-1) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma R-1-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.