Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice.
Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice.
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DOI：
10.1111/acer.12825
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Miczek KA
中科院分区：
文献类型：
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作者：
Albrechet-Souza L;Hwa LS;Han X;Zhang EY;DeBold JF;Miczek KA
大多数关于促肾上腺皮质激素释放因子 (CRF) 和乙醇消耗的研究都集中在 CRF 1 型 (CRF1) 受体；人们对 CRF 系统的其他成分知之甚少，例如 CRF 2 型 (CRF2) 受体和 CRF 结合蛋白 (CRFBP)。在人类中，CRFBP 基因中的几种核苷酸多态性与乙醇滥用有关。在暴露于乙醇暴饮模式（黑暗中饮酒，DID）或产生依赖的饮酒方案（两瓶选择，间歇性获取酒精，IAA）4周的C57BL/6J小鼠中，研究了CRFBP在腹侧被盖区（VTA）和杏仁核中央核（CeA）中的作用。还评估了 VTA CRFBP 和 CRF2 受体对乙醇暴饮的潜在相互作用。将 CRFBP 拮抗剂 CRF6-33 显微注射到 VTA 或 CeA 中，或将 CRF2 拮抗剂 Astressin2-B (A2B) 单独或与 CRF6-33 组合显微注射到 VTA 中，并使用 20% (w/v) 乙醇 4 小时 (DID)。不同组的小鼠在 VTA 或 CeA 中接受载体和一定剂量的 CRF6-33，并可以使用乙醇/水 24 小时 (IAA)。测量血液乙醇浓度（BEC），并确定因操作引起的惊厥而导致的戒断症状。在 DID 期间，VTA 内 CRF6-33 和 A2B 剂量依赖性地减少了小鼠的乙醇摄入量。此外，亚有效剂量的 CRF6-33 和较低剂量的 A2B 的组合可促进减轻乙醇暴饮的叠加效应。 VTA 内 CRF6-33 不影响给予 IAA 的小鼠的乙醇消耗，CeA 内 CRF6-33 不改变两种饮酒模型中的酒精消耗。 DID 和 IAA 促进药理学相关的 BEC，然而，只有给予 IAA 的小鼠在停药期间表现出惊厥事件。这些发现表明，VTA CRFBP 通过可能涉及 CRF2 受体的机制参与了乙醇饮用量增加的初始阶段。
Most studies with corticotropin releasing factor (CRF) and ethanol consumption have focused on CRF type 1 (CRF1) receptors; less is known about other components of the CRF system, such as the CRF type 2 (CRF2) receptors and the CRF binding protein (CRFBP). In humans, several nucleotide polymorphisms in the CRFBP gene have been associated with ethanol abuse. The role of the CRFBP within the ventral tegmental area (VTA) and the central nucleus of the amygdala (CeA) was investigated in C57BL/6J mice exposed to an ethanol binge drinking paradigm (drinking-in-the-dark, DID), or to a dependence-producing drinking protocol (two-bottle choice, intermittent access to alcohol, IAA) for 4 weeks. Potential interactions between VTA CRFBP and CRF2 receptors on ethanol binge drinking were also assessed. Mice were microinjected with the CRFBP antagonist CRF6–33 into the VTA or CeA, or with the CRF2 antagonist Astressin2-B (A2B) alone or in combination with CRF6–33 into the VTA, and had access to 20% (w/v) ethanol for 4 h (DID). Separate cohorts of mice received vehicle and doses of CRF6–33 into the VTA or CeA and had access to ethanol/water for 24 h (IAA). Blood ethanol concentrations (BECs) were measured, and signs of withdrawal by handling-induced convulsion were determined. Intra-VTA CRF6–33 and A2B reduced ethanol intake dose-dependently in mice during DID. Furthermore, a combination of a sub-effective dose of CRF6–33 and a lower dose of A2B promoted additive effects in attenuating ethanol binge drinking. Intra-VTA CRF6–33 did not affect ethanol consumption in mice given IAA, and intra-CeA CRF6–33 did not change alcohol consumption in both models of drinking. DID and IAA promoted pharmacologically relevant BECs, however, only mice given IAA exhibited convulsive events during withdrawal. These findings suggest that VTA CRFBP is involved in the initial stages of escalated ethanol drinking by mechanisms that may involve CRF2 receptors.