Elsevier

Brain Research

Volume 1314, 16 February 2010, Pages 38-43
Brain Research

Research Report
A ventral tegmental CRF–glutamate–dopamine interaction in addiction

https://doi.org/10.1016/j.brainres.2009.09.101Get rights and content

Abstract

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.

Section snippets

Behavioral studies

To explore the possibility that CRF-dependent reinstatement of cocaine-seeking by footshock might involve a CRF action at the level of midbrain dopamine neurons, the Wise group conducted a series of studies in which VTA microdialysis samples were taken and various agents were infused into the VTA by reverse dialysis. First, they prepared animals with chronic jugular catheters and VTA guide cannulae (for subsequent insertion of microdialysis probes) and trained them for two weeks to

Anatomical studies

In parallel with the microdialysis studies of the Wise group, the Morales group initiated anatomical studies on the possible basis for CRF–glutamate–dopamine interaction in the VTA. While the microdialysis studies subsequently showed important differences between cocaine-experienced and cocaine-naive rats, the initial anatomical studies were in cocaine-naive rats and provide an initial characterization of dopamine, glutamate, and CRF elements in the normal VTA.

These studies were designed first

Current status

An interaction of CRF with ventral tegmental glutamate signaling to dopamine neurons, implicated by the electrophysiological studies of Ungless et al. (2003) and first suggested by the histological studies of Swanson et al. (1983) and the intracranial injection studies of Kalivas et al. (1987), is confirmed by our microdialysis and anatomical studies. We have identified CRF–dopamine synapses (Tagliaferro and Morales, 2008) and detected and quantified stress-induced CRF release (Wang et al., 2005

Acknowledgments

Preparation of this manuscript was supported by NIH funding through the Intramural Research Program of the National Institute on Drug Abuse.

References (41)

  • BehanD.P. et al.

    Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders

    Mol. Psychiatry

    (1996)
  • BozarthM.A. et al.

    Toxicity associated with long-term intravenous heroin and cocaine self- administration in the rat

    J. Am. Med. Assoc.

    (1985)
  • DeutchA.Y. et al.

    Stress selectively increases fos protein in dopamine neurons innervating the prefrontal cortex

    Cereb. Cortex

    (1991)
  • ErbS. et al.

    A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on stress-induced reinstatement of cocaine seeking

    J. Neurosci.

    (1999)
  • ErbS. et al.

    Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period

    Psychopharmacology

    (1996)
  • ErbS. et al.

    The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

    J. Neurosci.

    (1998)
  • GeffenL.B. et al.

    Release of dopamine from dendrites in rat substantia nigra

    Nature

    (1976)
  • HahnJ. et al.

    Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons

    J. Neurosci.

    (2009)
  • HeinrichsS.C. et al.

    Corticotropin-releasing factor-binding protein ligand inhibitor blunts excessive weight gain in genetically obese Zucker rats and rats during nicotine withdrawal

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • JahnO. et al.

    The binding protein of corticotropin-releasing factor: ligand-binding site and subunit structure

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • Cited by (0)

    View full text