Orexin corticotropin releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine (2015)

J Neurosci. 2015 Apr 29;35(17):6639-53. doi: 10.1523/JNEUROSCI.4364-14.2015.

Navarro G1, Quiroz C2, Moreno-Delgado D1, Sierakowiak A2, McDowell K2, Moreno E1, Rea W2, Cai NS2, Aguinaga D1, Howell LA3, Hausch F4, Cortés A1, Mallol J1, Casadó V1, Lluís C1, Canela EI1, Ferré S5, McCormick PJ6.


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.