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

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

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: CRF receptor; GPCR heteromer; cocaine; orexin receptor; sigma receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / metabolism
  • Cocaine / pharmacology*
  • Cyclic AMP / metabolism
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects*
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Oncogene Protein v-akt / metabolism
  • Orexin Receptors / genetics
  • Orexin Receptors / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Time Factors
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects*
  • beta-Arrestins

Substances

  • Arrestins
  • Dopamine Uptake Inhibitors
  • Orexin Receptors
  • Receptors, Corticotropin-Releasing Hormone
  • beta-Arrestins
  • CRF receptor type 1
  • Cyclic AMP
  • Oncogene Protein v-akt
  • Cocaine
  • Dopamine