CRF modulation of NMDA Currents & Behavior in the VTA

描述（由申请人提供）：压力会增加成瘾行为，如行为敏感。尽管已有文献证明腹侧被盖区（VTA）是诱发行为敏感的关键脑区，但应激增加行为敏感的机制尚不清楚。本研究的主要目的是阐明促肾上腺皮质激素释放因子（CRF）介导NMDA受体功能和行为致敏的机制。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突触调节提供了第一个证据。具体来说，我们的数据表明，CRF激活crf2受体（CRF2R），其与CRF结合蛋白（CRF- bp）结合增加了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电流的增强代表了应激诱导的可卡因致敏的关键细胞现象。在具体目标1中，我们希望详细描述对CRF敏感的DA神经元子集的解剖投影。特异性目标2将定义由PLC激活的细胞内通路，该通路负责crf依赖性NMDA电流的增加。最后，具体目标3将研究CRF和CRF2R激动剂和拮抗剂在调节情境依赖性行为致敏和应激依赖性行为致敏中的作用。

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.