CRF Modulation of NMDA Currents and Behavior in the VTA

描述(由申请者提供)：压力会增加成瘾行为。促肾上腺皮质激素释放因子(CRF)在应激事件中在腹侧被盖区(VTA)释放，并导致对可卡因寻求的复发。然而，CRF导致寻求可卡因的应激依赖性复发的机制还知之甚少。本研究的主要目的是了解CRF-R1和CRF-R2以及VTA中CRF-BP在调节多巴胺释放和应激诱导的复吸可卡因中的作用。在过去的四年里，我的实验室收集的证据表明，CRF激活CRF-R2，增加VTA DA神经元中NMDAR介导的电流。此外，我们有证据表明，VTA DA神经元中CRF-R1的激活通过激活ih来增加放电活动。通过在VTA中进行膜片钳记录，特定的Aim 1将详细阐明：a)依赖CRFR1的放电频率增加的细胞内途径，以及b)VTA中依赖CRF-R2的NMDAR电流增加的细胞内途径。具体目的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依赖的通路在抑制足底电击诱导的对可卡因寻求的复发中的作用。最后，《特定目标4》将深入探讨CRF-BP。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上的理解。我们的结果可能会为阻断CRF-R1和CRF-R2对VTA神经元的依赖效应从而破坏应激诱导的可卡因寻求的药物创造新的治疗线索。与公共健康相关：压力会增加成瘾行为。然而，释放压力的分子对药物寻找产生负面影响的机制还知之甚少。本项目的主要目的是阐明CRFR1和CRFR2在促进应激增强的复吸可卡因过程中的作用。吸毒复发是一个主要的健康问题，至今仍无法治愈。这项提议的结果可能使我们能够创造新的治疗目标，旨在抑制应激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.