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

• Published in: Neuropharmacology 2014-07, Vol.82, p.28-40
• Main Authors: Nimitvilai, Sudarat, Herman, Melissa, You, Chang, Arora, Devinder S., McElvain, Maureen A., Roberto, Marisa, Brodie, Mark S.
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Central Nervous System Agents - pharmacology; Corticotropin-Releasing Hormone - agonists; Corticotropin-Releasing Hormone - metabolism; Desensitization; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine D2 receptor; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Glutamate; Glutamic Acid - metabolism; Male; Neurons - drug effects; Neurons - physiology; Patch-Clamp Techniques; Quinpirole; Quinpirole - pharmacology; Rats, Inbred F344; Rats, Wistar; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - metabolism; Receptors, Glutamate - metabolism; sEPSC; Urocortin; Urocortins - pharmacology; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - physiology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.03.006

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. •Dopamine inhibition reversal (DIR) is the process by which D2 receptors desensitize.•Glutamate receptor antagonists blocked induction but not maintenance of DIR.•Like D1 agonists, CRF and the CRF agonist urocortin promoted D2 desensitization.•Urocortin or D1 agonists increased sEPSCs only in presence of D2 agonist quinpirole.•Glutamate release in the VTA increases under the same conditions that produce DIR.