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

Gemma Navarro, César Quiroz, David Moreno-Delgado, Adam Sierakowiak, Kimberly McDowell, Estefanía Moreno, William Rea, Ning-Sheng Cai, David Aguinaga, Lesley A. Howell, Felix Hausch, Antonio Cortés, Josefa Mallol, Vicent Casadó, Carme Lluís, Enric I. Canela, Sergi Ferré, Peter J. McCormick

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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.
Original languageEnglish
Pages (from-to)6639-6653
Number of pages15
JournalThe Journal of Neuroscience
Issue number17
Publication statusPublished - 29 Apr 2015


  • cocaine
  • CRF receptor
  • GPCR heteromer
  • orexin receptor
  • sigma receptor

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