权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Enhanced CRF Signaling in the VTA Following Binge Drinking

酗酒后 VTA 中 CRF 信号增强

基本信息

批准号：
8109406
负责人：
DENNIS R. SPARTA
金额：
$ 5.3万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-16 至 2012-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109406
关键词：
Address Adolescent Alcohol abuse Alcohol consumption Alcoholism Behavior Blood Brain CRF receptor type 2 Chemosensitization Complement Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Disease Dopamine Drug abuse Electrophysiology (science)Ethanol Etiology Goals Heavy Drinking Hour In Vitro Infusion procedures Injection of therapeutic agent Lead Mediating Modeling Mus N-Methylaspartate Neurobiology Neuropeptides Peptides Plastics Procedures Protocols documentation Receptor Signaling Risk Factors Rodent Model Signal Pathway Signal Transduction Structure Techniques Testing Ventral Tegmental Area alcohol relapse alcohol response alcohol use disorder base binge drinking corticotropin releasing factor-binding protein dopaminergic neuron drinking human male in vivo inhibitor/antagonist mouse model neuromechanism novel patch clamp patient population problem drinker receptor relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): Binge and/or excessive drinking is a problematic component of alcoholism which has been correlated with enhanced alcohol use disorder in adolescents (Hingson et al., 2005; 2007; Miller et al. 2007). However, the neural mechanisms that mediate this behavior remain unclear. Here, we utilize a mouse model of binge and/or excessive drinking known as drinking in the dark (DID) to examine corticotropin releasing factor (CRF) signaling in the ventral tegmental area (VTA), a structure involved in the etiology of drug and alcohol abuse. In the DID model, C57BL/6J mice drink approximately 10 g/kg and achieve blood ethanol concentrations of approximately 100 mg/dL or 0.1%, which is equivalent to 4-6 drinks over a 2 hour period in a normal sized human male (Rhodes et al., 2005; 2007). CRF is a widely expressed neuropeptide that has been shown to modulate neurobiological responses to ethanol (for review see Koob, 2003). Preliminary data suggest that binge ethanol drinking in mice results in a greater CRF-induced potentiation of NMDA current in VTA dopamine (DA) neurons. However, the CRF receptor subtypes involved in this increased potentiation remain unknown. Therefore, Specific Aim I will examine which CRF receptor subtype mediates this increased NMDA potentiation. For this aim, I will employ patch-clamp electrophysiology. Specific Aim II will complement the first aim by examining whether intra-VTA administration of selective antagonists (CRFi receptor, CRF2 receptor, CRF-binding protein) reduces the high ethanol consumption associated with DID procedures. 1 hypothesize that binge drinking of ethanol becomes modulated by increased CRFi receptor signaling in the VTA and that blockade of the CRFi receptor in the VTA will reduce high ethanol consumption associated with excessive binge-like drinking. By utilizing both in vitro and in vivo techniques, I feel that I will fully be able to address the questions presented in this proposal. Results from this proposal will identify a possible pharmacological target (CRF signaling in the VTA) that may be useful in targeting specific alcoholic patient populations.

描述（由申请人提供）：酗酒和/或过量饮酒是酒精中毒的一个有问题的组成部分，其与青少年中增强的酒精使用障碍相关（Hingson等人，2005; 2007;米勒等人，2007）。然而，介导这种行为的神经机制仍不清楚。在这里，我们利用小鼠模型的狂欢和/或过度饮酒称为在黑暗中饮酒（DID）检查促肾上腺皮质激素释放因子（CRF）信号在腹侧被盖区（VTA），一个结构参与的病因药物和酒精滥用。在DID模型中，C57 BL/6 J小鼠饮用约10 g/kg并达到约100 mg/dL或0.1%的血液乙醇浓度，这相当于正常大小的人类男性在2小时内饮用4-6次（罗兹等人，2005; 2007）。CRF是一种广泛表达的神经肽，已显示可调节对乙醇的神经生物学反应（综述参见Koob，2003）。初步的数据表明，在小鼠中，酗酒导致更大的CRF诱导的增强腹侧被盖区多巴胺（DA）神经元的NMDA电流。然而，参与这种增强的CRF受体亚型仍然未知。因此，具体目标I将检查哪种CRF受体亚型介导这种增加的NMDA增强作用。为此，我将采用膜片钳电生理学。特异性目标II将通过检查VTA内给予选择性拮抗剂（CRF 1受体、CRF 2受体、CRF结合蛋白）是否减少与DID手术相关的高乙醇消耗量来补充第一个目标。1假设酒精的狂饮通过VTA中增加的CRFi受体信号传导而调节，并且VTA中CRFi受体的阻断将减少与过度狂饮相关的高酒精消耗。通过利用体外和体内技术，我认为我将完全能够解决本提案中提出的问题。该提案的结果将确定一个可能的药理学靶点（VTA中的CRF信号传导），该靶点可能适用于特定的酒精患者人群。