CRF Modulation of NMDA Currents and Behavior in the VTA

描述（由申请人提供）：压力增加成瘾行为。促肾上腺皮质激素释放因子（CRF）是释放在腹侧被盖区（VTA）在应激事件，并产生复发可卡因寻求。然而，CRF产生可卡因寻求的压力依赖性复发的机制知之甚少。本研究的主要目的是了解CRF-R1和CRF-R2以及CRF-BP在腹侧被盖区调节多巴胺释放和应激诱导的可卡因成瘾复发中的作用。在过去的四年里，我的实验室收集的证据表明，CRF激活CRF-R2，以增加腹侧被盖区DA神经元的NMDAR介导的电流。此外，我们有证据表明，CRF-R1激活腹侧被盖区DA神经元增加通过激活Ih的放电活动。通过在VTA中进行膜片钳记录，具体目标1将详细阐明：a）负责放电率CRFR 1依赖性增加的细胞内途径，和B）负责VTA中NMDAR电流CRF-R2依赖性增加的细胞内途径。具体目标2将确定CRF-R1和CRF-R2在调节腹侧纹状体DA释放中的作用。具体目标3将确定CRF-R1-和CRF-R2-依赖性途径在抑制足电击诱导的可卡因寻求复发中的作用。最后，具体目标4将对CRF-BP进行深入的机制研究。这项资助的结果将对CRF对VTA神经元的各种影响产生深刻的机制和行为理解。我们的研究结果可能会产生新的治疗药物，破坏CRF-R1和CRF-R2依赖性的影响腹侧被盖区神经元，从而应激诱导可卡因寻求。公共卫生相关性：压力会增加成瘾行为。然而，压力释放分子对药物寻求产生负面影响的机制却知之甚少。该项目的主要目标是阐明CRFR 1和CRFR 2在促进可卡因寻求的压力增强复发中的作用。重新寻求毒品是一个重大的健康问题，仍然没有治愈。该提案的结果可以使我们能够创建新的治疗目标，旨在抑制压力事件增加药物滥用复发的能力。

DESCRIPTION (provided by applicant): Stress increases addictive behaviors. Corticotropin-releasing factor (CRF) is released in the ventral tegmental area (VTA) during stressful events, and produces relapse to cocaine seeking. However, the mechanism by which CRF produces stress-dependent relapse to cocaine seeking is poorly understood. The main goal of this proposal is to understand the role of CRF-R1 and CRF-R2, and the CRF-BP in the VTA in modulating dopamine release and stress-induced relapse to cocaine seeking. Over the past four years, my laboratory has collected evidence showing that CRF activates CRF-R2 to increase NMDAR-mediated currents in VTA DA neurons. Furthermore, we have evidence that CRF-R1 activation in VTA DA neurons increases firing activity via activation of Ih. By performing patch-clamp recordings in the VTA, specific aim 1 will elucidate in detail: a) the intracellular pathway responsible for the CRFR1-dependent increase in firing rate, and b) the intracellular pathways responsible for the CRF-R2-dependent increase in NMDAR currents in the VTA. Specific aim 2 will determine the role of CRF-R1 and CRF-R2 in modulating DA release in the ventral striatum. Specific aim 3 will determine the role of CRF-R1- and CRF-R2-dependent pathways in inhibiting footshock- induced relapse to cocaine seeking. Finally, specific aim 4 will take a deep mechanistic look at the CRF-BP. The results from this grant will produced a deep mechanistic and behavioral understanding of the various effects of CRF on VTA neurons. Our results will likely create new therapeutic leads toward agents that disrupt the CRF-R1- and CRF- R2-dependent effects on VTA neurons and thus stress-induced cocaine seeking. PUBLIC HEALTH RELEVANCE: Stress increases addictive behavior. However, the mechanism by which stress-released molecules exert their negative effects on drug-seeking are poorly understood. The main goal of this project is to elucidate the role of CRFR1 and CRFR2 in promoting stress-enhanced relapse to cocaine seeking. Relapse to drug seeking is a major health problem that still has no cure. The results from this proposal could enable us to create new therapeutic targets aimed at inhibiting the ability of stressful event to increase relapse to substance abuse.