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Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release.

Neuropharmacology (2014-03-25)
Sudarat Nimitvilai, Melissa Herman, Chang You, Devinder S Arora, Maureen A McElvain, Marisa Roberto, Mark S Brodie
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lamotrigine, ≥98%, powder
Lamotrigine for system suitability, European Pharmacopoeia (EP) Reference Standard
USP
Lamotrigine, United States Pharmacopeia (USP) Reference Standard
Lamotrigine for peak identification, European Pharmacopoeia (EP) Reference Standard
Lamotrigine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
(+)-Bicuculline, ≥97.0% (TLC)
Supelco
Lamotrigine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
CNQX, ≥98% (HPLC), solid