Enhanced CRF Signaling in the VTA Following Binge Drinking

酗酒后 VTA 中 CRF 信号增强

• 批准号: 8116096
• 负责人: DENNIS R. SPARTA
• 金额: $ 4.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2012-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116096
• 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.

说明(由申请人提供)：酗酒和/或过度饮酒是酒精中毒的一个有问题的组成部分，它与青少年酒精使用障碍的增加有关(Hingson等人，2005；2007；Miller等人)。2007)。然而，调节这种行为的神经机制仍然不清楚。在这里，我们利用一种被称为黑暗中饮酒(DID)的酗酒和/或过度饮酒的小鼠模型来检测腹侧被盖区(VTA)中促肾上腺皮质激素释放因子(CRF)的信号，该结构参与了药物和酒精滥用的病因学。在DID模型中，C57BL/6J小鼠饮酒量约为10g/kg，血液中乙醇浓度约为100 mg/dL或0.1%，相当于一个正常体型的男性在2小时内饮用4-6杯酒(Rhodes等人，2005；2007)。CRF是一种广泛表达的神经肽，已被证明可调节对乙醇的神经生物学反应(参见Koob，2003)。初步数据表明，狂饮酒精会导致CRF诱导的VTA多巴胺(DA)神经元NMDA电流的增强。然而，参与这种增强的CRF受体亚型仍不清楚。因此，特定的目的我将研究CRF受体亚型介导这种NMDA增强。为此，我将采用膜片钳电生理学。特殊目的II将通过检查VTA内给予选择性拮抗剂(cRFI受体、CRF2受体、CRF结合蛋白)是否减少与DID手术相关的高酒精消耗来补充第一个目的。1假设狂饮酒精受到VTA中cRFI受体信号增加的调节，阻断VTA中的cRFI受体将减少与过度酗酒相关的高酒精消耗。通过利用体外和体内技术，我觉得我将完全能够解决这项提案中提出的问题。这项建议的结果将确定一个可能的药理靶点(VTA中的CRF信号)，该靶点可能对特定的酒精中毒患者群体有用。