Enhanced CRF Signaling in the VTA Following Binge Drinking

酗酒后 VTA 中 CRF 信号增强

• 批准号: 8102278
• 负责人: DENNIS R. SPARTA
• 金额: $ 0.14万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-16 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102278
• 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; Electrophysiology (science); Ethanol; Etiology; Figs - dietary; Goals; Heavy Drinking; Hour; In Vitro; Infusion procedures; Injection of therapeutic agent; Lead; Mediating; Modeling; Mus; N-Methylaspartate; Neurobiology; Neuropeptides; Peptides; Pharmaceutical Preparations; 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

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）：暴饮暴食和/或过度饮酒是酗酒的一个有问题的组成部分，与青少年酒精使用障碍的加重有关（Hingson 等人，2005 年；2007 年；Miller 等人，2007 年）。然而，介导这种行为的神经机制仍不清楚。在这里，我们利用暴饮暴食和/或过度饮酒（称为黑暗饮酒（DID））的小鼠模型来检查腹侧被盖区（VTA）中的促肾上腺皮质激素释放因子（CRF）信号传导，VTA是与药物和酒精滥用的病因学有关的结构。在 DID 模型中，C57BL/6J 小鼠饮酒约 10 g/kg，血液乙醇浓度约为 100 mg/dL 或 0.1%，相当于正常体型的男性在 2 小时内饮酒 4-6 次（Rhodes 等，2005；2007）。 CRF 是一种广泛表达的神经肽，已被证明可以调节对乙醇的神经生物学反应（综述参见 Koob，2003）。初步数据表明，小鼠暴饮乙醇会导致 CRF 诱导的 VTA 多巴胺 (DA) 神经元 NMDA 电流增强。然而，参与这种增强作用的 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 NMDA 增强的增强。为了这个目的，我将采用膜片钳电生理学。具体目标 II 将通过检查 VTA 内施用选择性拮抗剂（CRFi 受体、CRF2 受体、CRF 结合蛋白）是否减少与 DID 手术相关的高乙醇消耗来补充第一个目标。 1 假设过量饮酒会受到 VTA 中 CRFi 受体信号增加的调节，并且阻断 VTA 中的 CRFi 受体将减少与过度暴饮相关的高乙醇消耗。通过利用体外和体内技术，我认为我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目标（VTA 中的 CRF 信号传导），该目标可能有助于针对特定的酒精患者群体。