title: Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release.
abstract: Neurons of the ventral tegmental area (VTA) are the source of dopaminergic (DAergic) input to important brain regions related to addiction. Prolonged exposure of these VTA neurons to moderate concentrations of dopamine (DA) causes a time-dependent decrease in DA-induced inhibition, a complex desensitization called DA inhibition reversal (DIR). DIR is mediated by conventional protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of some Gq-linked receptors. Corticotropin releasing factor (CRF) acts via Gq, and can modulate glutamater neurotransmission in the VTA. In the present study, we used brain slice electrophysiology to characterize the interaction of DA, glutamate antagonists, and CRF agonists in the induction and maintenance of DIR in the VTA. Glutamate receptor antagonists blocked induction but not maintenance of DIR. Putative blockers of neurotransmitter release and store-operated calcium channels blocked and reversed DIR. CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole, consistent with our earlier work indicating that Gq activation reverses quinpirole-mediated inhibition. In whole cell recordings, the combination of urocortin and quinpirole, but not either agent alone, increased spontaneous excitatory postsynaptic currents (sEPSCs) in VTA neurons. Likewise, the combination of a D1-like receptor agonist and quinpirole, but not either agent alone, increased sEPSCs in VTA neurons. In summary, desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA.
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Room E-202, M/C 901, Chicago, IL 60612-7342, USA.
authors.forename: Sudarat
authors.initials: S
authors.lastname: Nimitvilai
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, SP30-1150, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Herman
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Room E-202, M/C 901, Chicago, IL 60612-7342, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: You
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Room E-202, M/C 901, Chicago, IL 60612-7342, USA.
authors.forename: Devinder S
authors.initials: DS
authors.lastname: Arora
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Room E-202, M/C 901, Chicago, IL 60612-7342, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McElvain
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, SP30-1150, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Room E-202, M/C 901, Chicago, IL 60612-7342, USA. Electronic address: mbrodie@uic.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Brodie
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019257:Quinpirole / Q000494:pharmacology; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D054832:Urocortins / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
chemical_list: D002491:Central Nervous System Agents; D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D017470:Receptors, Glutamate; D054832:Urocortins; D019257:Quinpirole; D018698:Glutamic Acid; D003346:Corticotropin-Releasing Hormone; D004298:Dopamine
keywords: Desensitization; Dopamine D2 receptor; Glutamate; Quinpirole; Urocortin; sEPSC