Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California.
Alcohol Clin Exp Res. 2013 Oct;37(10):1680-7. doi: 10.1111/acer.12153. Epub 2013 Jun 13.
Corticotropin releasing factor (CRF) and urocortin play an important role in many stress responses and also can regulate ethanol (EtOH) intake. Adaptations in CRF signaling in the central amygdala promote EtOH consumption after long-term EtOH intake in dependent animals and also after brief periods of binge EtOH intake. Thus, even brief episodes of EtOH consumption can alter the function of the CRF system, allowing CRF to regulate EtOH intake. Here, we examined whether brief binge EtOH consumption leads to CRF receptor adaptations within the ventral tegmental area (VTA), a structure involved in signaling rewarding and aversive events and important in the development and expression of drug and alcohol addiction.
We utilized a mouse model of binge drinking known as drinking in the dark (DID), where C57BL/6J mice drink approximately 6 g/kg in 4 hours and achieve blood EtOH concentrations of approximately 100 mg/dl, which is equivalent to binge drinking in humans. We used ex vivo whole-cell recordings from putative VTA dopamine (DA) neurons to examine CRF regulation of NMDA receptor (NMDAR) currents. We also examined the impact of CRF receptor antagonist injection in the VTA on binge EtOH intake.
Ex vivo whole-cell recordings from putative VTA DA neurons showed enhanced CRF-mediated potentiation of NMDAR currents in juvenile mice that consumed EtOH in the DID procedure. CRF-induced potentiation of NMDAR currents in EtOH-drinking mice was blocked by administration of CP-154,526 (3 μM), a selective CRF1 receptor antagonist. Furthermore, intra-VTA infusion of CP-154,526 (1 μg) significantly reduced binge EtOH consumption in adult mice. These results were not due to alterations of VTA NMDAR number or function, suggesting that binge drinking may enhance signaling through VTA CRF1 receptors onto NMDARs.
Altered CRF1 receptor-mediated signaling in the VTA promotes binge-like EtOH consumption in mice, which supports the idea that CRF1 receptors may therefore be a promising pharmacological target for reducing binge drinking in humans.
促肾上腺皮质释放因子（CRF）和尿皮质素在许多应激反应中发挥重要作用，也可以调节乙醇（EtOH）的摄入。在依赖动物长期摄入 EtOH 后以及短暂的 binge EtOH 摄入后，中央杏仁核中 CRF 信号的适应性会促进 EtOH 的消耗。因此，即使是短暂的 EtOH 摄入也会改变 CRF 系统的功能，从而允许 CRF 调节 EtOH 的摄入。在这里，我们研究了短暂的 binge EtOH 消耗是否会导致腹侧被盖区（VTA）内的 CRF 受体适应性，VTA 是参与信号传递奖赏和厌恶事件的结构，对药物和酒精成瘾的发展和表达很重要。
我们利用了一种称为暗饮（DID）的 binge 饮酒小鼠模型，其中 C57BL/6J 小鼠在 4 小时内饮用约 6 g/kg 的乙醇，达到约 100 mg/dl 的血液 EtOH 浓度，相当于人类的 binge 饮酒。我们使用来自 VTA 中假定的多巴胺（DA）神经元的体外全细胞记录来研究 CRF 对 NMDA 受体（NMDAR）电流的调节。我们还研究了 VTA 中 CRF 受体拮抗剂注射对 binge EtOH 摄入的影响。
来自 VTA 中假定的 DA 神经元的体外全细胞记录显示，在接受 DID 程序中 EtOH 消耗的幼年小鼠中，CRF 介导的 NMDAR 电流增强。在 EtOH 饮用小鼠中，CRF 诱导的 NMDAR 电流增强被 CP-154,526（3 μM）阻断，CP-154,526 是一种选择性的 CRF1 受体拮抗剂。此外，VTA 内 CP-154,526（1 μg）的输注显著减少了成年小鼠的 binge EtOH 消耗。这些结果不是由于 VTA NMDAR 数量或功能的改变引起的，这表明 binge 饮酒可能会增强 VTA CRF1 受体对 NMDAR 的信号传递。
VTA 中 CRF1 受体介导的信号转导改变促进了小鼠 binge 样 EtOH 消耗，这支持了 CRF1 受体可能是减少人类 binge 饮酒的有前途的药理学靶点的观点。
