CRF modulation of NMDA Currents & Behavior in the VTA

NMDA 电流的 CRF 调制

• 批准号: 7039156
• 负责人: ANTONELLO BONCI
• 金额: $ 27.63万
• 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/7039156
• 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）：压力增加了成瘾行为，例如行为敏感性。尽管已经有充分的文献证明，腹侧对接区域（VTA）是大脑区域，其激活对于诱导行为敏化至关重要，但压力增加行为敏化的机制尚不清楚。该提案的主要目的是阐明皮质激素释放因子（CRF）介导NMDA受体功能和行为敏化的机制。我们的初步数据提供了第一个证据，证明了通过VTA多巴胺（DA）神经元子类的CRF直接进行突触传播的直接突触调节。具体而言，我们的数据表明，CRF激活CRF 2受体（CRF2R），该受体与CRF结合蛋白（CRF-BP）结合使用会增加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电流的增强代表了基础应力诱导的可卡因敏化的关键细胞现象。在特定目标1中，我们希望详细描述对CRF敏感的DA神经元子集的解剖学投影。特定的目标2将定义由PLC激活的细胞内途径，该途径负责CRF依赖性NMDA电流的增加。最后，特定的目标3将研究CRF和CRF2R激动剂和拮抗剂在调节上下文依赖性行为敏化和应激依赖性行为对可卡因的作用。