Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 17, Pages 6639-6653Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4364-14.2015
Keywords
cocaine; CRF receptor; GPCR heteromer; orexin receptor; sigma receptor
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Funding
- intramural funds of the National Institute on Drug Abuse
- Spanish Ministry of Science and Technology [SAF2011-23813, SAF2009-07276]
- Government of Catalonia Grant [2009-SGR-12]
- Center for Biomedical Research in Neurodegenerative Diseases Network Grant [CB06/05/0064]
- Ramon y Cajal Fellowship
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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 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.
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