Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
PLoS One. 2011;6(10):e26997. doi: 10.1371/journal.pone.0026997. Epub 2011 Oct 28.
Converging lines of evidence point to the involvement of neurons of the centrally projecting Edinger-Westphal nucleus (EWcp) containing the neuropeptide Urocortin-1 (Ucn1) in excessive ethanol (EtOH) intake and EtOH sensitivity. Here, we expanded these previous findings by using a continuous-access, two-bottle choice drinking paradigm (3%, 6%, and 10% EtOH vs. tap water) to compare EtOH intake and EtOH preference in Ucn1 genetic knockout (KO) and wild-type (WT) mice. Based on previous studies demonstrating that electrolytic lesion of the EWcp attenuated EtOH intake and preference in high-drinking C57BL/6J mice, we also set out to determine whether EWcp lesion would differentially alter EtOH consumption in Ucn1 KO and WT mice. Finally, we implemented well-established place conditioning procedures in KO and WT mice to determine whether Ucn1 and the corticotropin-releasing factor type-2 receptor (CRF-R2) were involved in the rewarding and aversive effects of EtOH (2 g/kg, i.p.). Results from these studies revealed that (1) genetic deletion of Ucn1 dampened EtOH preference only in mice with an intact EWcp, but not in mice that received lesion of the EWcp, (2) lesion of the EWcp dampened EtOH intake in Ucn1 KO and WT mice, but dampened EtOH preference only in WT mice expressing Ucn1, and (3) genetic deletion of Ucn1 or CRF-R2 abolished the conditioned rewarding effects of EtOH, but deletion of Ucn1 had no effect on the conditioned aversive effects of EtOH. The current findings provide strong support for the hypothesis that EWcp-Ucn1 neurons play an important role in EtOH intake, preference, and reward.
越来越多的证据表明，含有神经肽 Urocortin-1 (Ucn1) 的中枢投射性 Edinger-Westphal 核（EWcp）神经元参与了过量乙醇（EtOH）摄入和 EtOH 敏感性。在这里，我们使用连续接入、双瓶选择饮用范式（3%、6%和 10% EtOH 与自来水相比），对 Ucn1 基因敲除（KO）和野生型（WT）小鼠进行比较，扩展了这些先前的发现。基于先前的研究表明，EWcp 的电解损伤减轻了高饮酒 C57BL/6J 小鼠的 EtOH 摄入和偏好，我们还着手确定 EWcp 损伤是否会以不同的方式改变 Ucn1 KO 和 WT 小鼠的 EtOH 消耗。最后，我们在 KO 和 WT 小鼠中实施了成熟的位置条件程序，以确定 Ucn1 和促肾上腺皮质素释放因子 2 型受体（CRF-R2）是否参与了 EtOH（2 g/kg，ip）的奖赏和厌恶效应。这些研究的结果表明：（1）Ucn1 的基因缺失仅在 EWcp 完整的小鼠中减弱了 EtOH 的偏好，但在接受 EWcp 损伤的小鼠中没有，（2）EWcp 的损伤减弱了 Ucn1 KO 和 WT 小鼠的 EtOH 摄入，但仅在表达 Ucn1 的 WT 小鼠中减弱了 EtOH 的偏好，（3）Ucn1 或 CRF-R2 的基因缺失消除了 EtOH 的条件性奖赏效应，但 Ucn1 的缺失对 EtOH 的条件性厌恶效应没有影响。目前的研究结果为 EWcp-Ucn1 神经元在 EtOH 摄入、偏好和奖赏中发挥重要作用的假设提供了强有力的支持。
