CRF modulation of NMDA Currents & Behavior in the VTA

NMDA 电流的 CRF 调制

• 批准号: 6775287
• 负责人: ANTONELLO BONCI
• 金额: $ 28.3万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775287
• 关键词: NMDA receptors; behavioral /social science research tag; behavioral habituation /sensitization; binding proteins; cocaine; corticotropin releasing factor; dopamine; dopamine agonists; dopamine antagonists; drug addiction; electrophysiology; hormone receptor; hormone regulation /control mechanism; laboratory mouse; membrane potentials; microinjections; neural transmission; neurons; neurotransmitter antagonist; phospholipase C; physiologic stressor; posttranslational modifications; protein kinase C; stereotaxic techniques; tegmentum; voltage /patch clamp

DESCRIPTION (provided by applicant): Stress increases addictive behaviors such as behavioral sensitization. Although it has been well documented that the ventral tegmental area (VTA) is the brain region whose activation is essential to induce behavioral sensitization, the mechanism through which stress increases behavioral sensitization is unknown. The main goal of this proposal is to elucidate the mechanism through which the corticotropin releasing factor (CRF) mediates NMDA receptor function and behavioral sensitization. Our preliminary data provide the first evidence for a direct synaptic modulation by CRF of synaptic transmission on a subclass of VTA dopamine (DA) neurons. Specifically, our data show that CRF activates CRF 2 receptors (CRF2R), which in combination with the CRF binding-protein (CRF-BP) increases NMDA currents in the VTA. Further, our data show that the CRF-dependent increase of NMDA currents in the VTA depends on the activation of phospholipase C (PLC) and PKC. We hypothesize that the potentiation of NMDA currents by CRF and the CRF-BP represents a key cellular phenomenon underlying stress-induced sensitization to cocaine. In specific aim 1, we want to characterize in detail the anatomical projections of the subset of DA neurons that are sensitive to CRF. Specific aim 2 will define the intracellular pathway activated by PLC that is responsible for the CRF-dependent increase of NMDA currents. Finally, specific aim 3 will study the role of CRF and of CRF2R agonists and antagonists in modulating context-dependent behavioral sensitization and stress-dependent behavioral sensitization to cocaine.

描述（由申请人提供）：压力会增加成瘾行为，例如行为过敏。尽管有充分证据表明，腹侧被盖区（VTA）是其激活对于诱导行为敏感性至关重要的大脑区域，但压力增加行为敏感性的机制尚不清楚。该提案的主要目标是阐明促肾上腺皮质激素释放因子 (CRF) 介导 NMDA 受体功能和行为敏化的机制。我们的初步数据为 CRF 对 VTA 多巴胺 (DA) 神经元亚类突触传递的直接调节提供了第一个证据。具体来说，我们的数据显示 CRF 激活 CRF 2 受体 (CRF2R)，它与 ​​CRF 结合蛋白 (CRF-BP) 结合增加 VTA 中的 NMDA 电流。此外，我们的数据表明，VTA 中 NMDA 电流的 CRF 依赖性增加取决于磷脂酶 C (PLC) 和 PKC 的激活。我们假设 CRF 和 CRF-BP 对 NMDA 电流的增强代表了压力诱导对可卡因过敏的关键细胞现象。在具体目标 1 中，我们想要详细描述对 CRF 敏感的 DA 神经元子集的解剖学投影。具体目标 2 将定义由 PLC 激活的细胞内通路，该通路负责 NMDA 电流的 CRF 依赖性增加。最后，具体目标 3 将研究 CRF 以及 CRF2R 激动剂和拮抗剂在调节可卡因的情境依赖性行为敏化和压力依赖性行为敏化中的作用。