A ventral tegmental CRF-glutamate-dopamine interaction in addiction.

Stress-induced reinstatement of cocaine-seeking is blocked by antagonists for the stress-related neurohormone corticotropin-releasing factor (CRF). One site of this action is the ventral tegmental area (VTA), where mild footshock stress causes CRF release, glutamate release, and dopaminergic activation in cocaine-experienced but not cocaine-naive animals. Infusion of CRF into VTA has similar effects to footshock in cocaine-experienced animals but fails to cause significant VTA glutamate release or dopaminergic activation in cocaine-naive animals. The reinstatement, glutamate release, and dopamine release are prevented by VTA infusions of CRF-receptor 2 (CRF-R2) but not CRF-R1 antagonists. Reinstatement is triggered by some but not all CRF-R2 agonists and some but not all CRF-R1 agonists; the common denominator of the effective agonists is that they bind to the CRF-binding protein (CRF-BP), which appears to be essential for the behavioral and VTA effects of stress and CRF in cocaine-experienced animals. In situ hybridization reveals mRNA for CRF-R1 and CRF-BP but not CRF-R2 in a subset of VTA dopamine neurons. Electron microscopy reveals primarily asymmetric synapses between a subset of VTA terminals containing glutamate and CRF and a subset of VTA dopaminergic neurons and primarily symmetric synapses between a subset of CRF terminals that do not contain glutamate and a subset of GABAergic neurons in VTA. Thus, a complex and not yet fully understood interaction of CRF, glutamate, and the mesocorticolimbic dopamine system is established by experience with cocaine, and this alteration appears to contribute importantly to the transition from casual to compulsive cocaine-seeking. Published by Elsevier B.V.