Enhanced CRF Signaling in the VTA Following Binge Drinking

描述（由申请人提供）：暴饮和/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加剧有关（Hingson等人，2005;2007；Miller等人，2007）。然而，介导这种行为的神经机制尚不清楚。在这里，我们利用暴饮和/或过度饮酒的小鼠模型（称为黑暗饮酒（DID））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，该结构涉及药物和酒精滥用的病因学。在DID模型中，C57BL/6J小鼠饮用约10 g/kg，血液乙醇浓度约为100 mg/dL或0.1%，相当于正常体型男性在2小时内饮用4-6次（Rhodes et al., 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（回顾见Koob， 2003）。初步数据表明，小鼠酗酒酒精导致更大的crf诱导的VTA多巴胺（DA）神经元的NMDA电流增强。然而，参与这种增强的CRF受体亚型仍然未知。因此，特异性目的1将检查哪种CRF受体亚型介导这种增加的NMDA增强。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。我假设酒精的狂饮受到VTA中CRFi受体信号增加的调节，并且VTA中CRFi受体的阻断将减少与过度狂欢样饮酒相关的高乙醇消耗。通过利用体外和体内技术，我觉得我将完全能够解决这个提案中提出的问题。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），这可能对特定的酒精患者群体有用。

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.