CRF Modulation of NMDA Currents and Behavior in the VTA

NMDA 电流的 CRF 调制和 VTA 中的行为

• 批准号: 7736205
• 负责人: ANTONELLO BONCI
• 金额: $ 37万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736205
• 关键词: Addictive Behavior; Affect; Agonist; Anatomy; Behavior; Behavioral; Brain; Brain region; Chemosensitization; Cocaine; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cyclic AMP-Dependent Protein Kinases; Detection; Dopamine; Event; Extinction (Psychology); Future; Goals; Grant; Health; In Vitro; Laboratories; Link; Mediating; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Process; Production; Protein Isoforms; Receptor Activation; Relapse; Role; Self Administration; Signal Pathway; Signal Transduction; Stress; Stressful Event; Substance abuse problem; Synapses; Testing; Ventral Striatum; Ventral Tegmental Area; Work; corticotropin releasing factor-binding protein; dopaminergic neuron; footshock induced; in vivo; new therapeutic target; novel therapeutics; patch clamp; prevent; public health relevance; research study; response; trafficking

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.

描述（由申请人提供）：压力会增加成瘾行为。在应激事件期间，促肾上腺皮质激素释放因子（CRF）在腹侧被盖区（VTA）释放，并导致对可卡因的复发。然而，CRF 导致应激依赖性可卡因复发的机制尚不清楚。该提案的主要目标是了解 CRF-R1 和 CRF-R2 以及 VTA 中的 CRF-BP 在调节多巴胺释放和压力诱导的可卡因寻求复发中的作用。在过去的四年里，我的实验室收集的证据表明，CRF 激活 CRF-R2 来增加 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 Ih 的激活来增加放电活动。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 CRFR1 依赖性放电率增加的细胞内途径，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部电击引起的可卡因寻求复发中的作用。最后，具体目标 4 将对 CRF-BP 进行深入的机械研究。这笔资助的结果将使人们对 CRF 对 VTA 神经元的各种影响产生深入的机制和行为理解。我们的研究结果可能会为破坏 VTA 神经元的 CRF-R1 和 CRF-R2 依赖效应的药物创造新的治疗线索，从而破坏压力诱导的可卡因寻找。公共卫生相关性：压力会增加成瘾行为。然而，人们对压力释放分子对药物寻求产生负面影响的机制知之甚少。该项目的主要目标是阐明 CRFR1 和 CRFR2 在促进压力增强的可卡因寻求复发中的作用。吸毒复发是一个仍无法治愈的主要健康问题。该提案的结果可以使我们创建新的治疗目标，旨在抑制压力事件增加药物滥用复发的能力。