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

doi:10.1523/JNEUROSCI.4364-14.2015

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

School of Pharmacy

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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.

Original language	English
Pages (from-to)	6639-6653
Number of pages	15
Journal	The Journal of Neuroscience
Volume	35
Issue number	17
DOIs	https://doi.org/10.1523/JNEUROSCI.4364-14.2015
Publication status	Published - 29 Apr 2015

Keywords

cocaine
CRF receptor
GPCR heteromer
orexin receptor
sigma receptor

Access to Document

10.1523/JNEUROSCI.4364-14.2015

Navarro et al (2015)
Articles are released under a Creative Commons Attribution License after a 6 months embargo
Final published version, 3.66 MB

Cite this

Navarro, G., Quiroz, C., Moreno-Delgado, D., Sierakowiak, A., McDowell, K., Moreno, E., Rea, W., Cai, N-S., Aguinaga, D., Howell, L. A., Hausch, F., Cortés, A., Mallol, J., Casadó, V., Lluís, C., Canela, E. I., Ferré, S., & McCormick, P. J. (2015). Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. The Journal of Neuroscience, 35(17), 6639-6653. https://doi.org/10.1523/JNEUROSCI.4364-14.2015

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 ; McCormick, Peter J. / Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. In: The Journal of Neuroscience. 2015 ; Vol. 35, No. 17. pp. 6639-6653.

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

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.",

keywords = "cocaine, CRF receptor, GPCR heteromer, orexin receptor, sigma receptor",

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Navarro, G, Quiroz, C, Moreno-Delgado, D, Sierakowiak, A, McDowell, K, Moreno, E, Rea, W, Cai, N-S, Aguinaga, D, Howell, LA, Hausch, F, Cortés, A, Mallol, J, Casadó, V, Lluís, C, Canela, EI, Ferré, S & McCormick, PJ 2015, 'Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine', The Journal of Neuroscience, vol. 35, no. 17, pp. 6639-6653. https://doi.org/10.1523/JNEUROSCI.4364-14.2015

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; McCormick, Peter J.

In: The Journal of Neuroscience, Vol. 35, No. 17, 29.04.2015, p. 6639-6653.

Research output: Contribution to journal › Article › peer-review

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AU - Navarro, Gemma

AU - Quiroz, César

AU - Moreno-Delgado, David

AU - Sierakowiak, Adam

AU - McDowell, Kimberly

AU - Moreno, Estefanía

AU - Rea, William

AU - Cai, Ning-Sheng

AU - Aguinaga, David

AU - Howell, Lesley A.

AU - Hausch, Felix

AU - Cortés, Antonio

AU - Mallol, Josefa

AU - Casadó, Vicent

AU - Lluís, Carme

AU - Canela, Enric I.

AU - Ferré, Sergi

AU - McCormick, Peter J.

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KW - CRF receptor

KW - GPCR heteromer

KW - orexin receptor

KW - sigma receptor

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DO - 10.1523/JNEUROSCI.4364-14.2015

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