Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons.
Stress increases addictive behaviors and is a common cause of relapse. Corticotropin-releasing factor (CRF) plays a key role in the modulation of drug taking by stress. However, the mechanism by which CRF modulates neuronal activity in circuits involved in drug addiction is poorly understood. Here we show that CRF induces a potentiation of NMDAR (N-methyl-D-aspartate receptor)-mediated synaptic transmission in dopamine neurons of the ventral tegmental area (VTA). This effect involves CRF receptor 2 (CRF-R2) and activation of the phospholipase C (PLC)-protein kinase C (PKC) pathway. We also find that this potentiation requires CRF binding protein (CRF-BP). Accordingly, CRF-like peptides, which do not bind the CRF-BP with high affinity, do not potentiate NMDARs. These results provide evidence of the first specific roles for CRF-R2 and CRF-BP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for both drugs of abuse and stress.
Ungless
Mark A
MA
Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, San Francisco, California 94110, USA.
Singh
Vineeta
V
Crowder
Tara L
TL
Yaka
Rami
R
Ron
Dorit
D
Bonci
Antonello
A
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
C101531:CRF receptor type 2; D002352:Carrier Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; C067133:corticotropin releasing factor-binding protein; D003346:Corticotropin-Releasing Hormone; D004298:Dopamine