Nimitvilai Sudarat, Herman Melissa, You Chang, Arora Devinder S, McElvain Maureen A, Roberto Marisa, Brodie Mark S
Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Room E-202, M/C 901, Chicago, IL 60612-7342, USA.
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, SP30-1150, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuropharmacology. 2014 Jul;82:28-40. doi: 10.1016/j.neuropharm.2014.03.006. Epub 2014 Mar 19.
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.
腹侧被盖区（VTA）的神经元是向与成瘾相关的重要脑区输入多巴胺能（DAergic）信号的来源。这些VTA神经元长期暴露于中等浓度的多巴胺（DA）会导致DA诱导的抑制作用出现时间依赖性降低，这是一种称为DA抑制逆转（DIR）的复杂脱敏现象。DIR由传统蛋白激酶C（cPKC）介导，通过同时刺激D2和D1样DA受体，或通过D2刺激与某些Gq偶联受体的激活同时发生来实现。促肾上腺皮质激素释放因子（CRF）通过Gq起作用，并可调节VTA中的谷氨酸能神经传递。在本研究中，我们使用脑片电生理学来表征DA、谷氨酸拮抗剂和CRF激动剂在VTA中DIR的诱导和维持过程中的相互作用。谷氨酸受体拮抗剂阻断了DIR的诱导，但没有阻断其维持。推测的神经递质释放阻滞剂和储存操纵性钙通道阻滞剂阻断并逆转了DIR。CRF和CRF激动剂尿皮质素逆转了D2激动剂喹吡罗产生的抑制作用，这与我们早期的工作一致，表明Gq激活可逆转喹吡罗介导的抑制作用。在全细胞记录中，尿皮质素和喹吡罗的组合，但不是单独使用任何一种药物，增加了VTA神经元中的自发性兴奋性突触后电流（sEPSCs）。同样，D1样受体激动剂和喹吡罗的组合，但不是单独使用任何一种药物，增加了VTA神经元中的sEPSCs。总之，多巴胺或CRF在DA能VTA神经元上诱导的D2受体脱敏与VTA中谷氨酸能信号的增加有关。
