Locally-generated Acetaldehyde Contributes to the Effects of Ethanol on Neurosteroids and LTP in the Hippocampus.
Locally-generated Acetaldehyde Contributes to the Effects of Ethanol on Neurosteroids and LTP in the Hippocampus.
复制标题
局部产生的乙醛有助于乙醇对海马神经类固醇和 LTP 的影响。
DOI：
10.1111/ncn3.39
复制
发表时间：
2013
影响因子：
0.4
通讯作者：
Zorumski,CharlesF
中科院分区：
文献类型：
--
作者：
Tokuda,Kazuhiro;Izumi,Yukitoshi;Zorumski,CharlesF
重度酒精中毒会损害记忆功能，高浓度乙醇（60 mmol L−1）会严重抑制大鼠海马切片中的长时程增强（LTP），这是一种学习和记忆的细胞模型。神经类固醇参与了LTP抑制。我们最近报道了60 mmol L−1乙醇的抑制作用被4‐甲基吡唑（4MP）阻断，4‐甲基吡唑是一种酒精脱氢酶抑制剂，这表明海马体内局部产生的乙醛参与了LTP抑制。我们研究了乙醇代谢产生的乙醛是否有助于神经甾体生成和LTP抑制。结果与60 mmol L−1乙醇一样，我们发现外源性乙醛增强了CA1锥体神经元的神经类固醇免疫染色，并且仅高乙醇增强的神经类固醇免疫染色被4MP阻断，而不被其他乙醇代谢途径的抑制剂阻断。60 mmol L−1乙醇对LTP的抑制作用类似于较低浓度的乙醇（20 mmol L−1）加乙醛（60 μmol L−1），尽管在这些浓度下单独使用两种剂都无效，这表明60 mmol L−1乙醇通过多种作用抑制LTP，其中一种作用涉及乙醛，另一种作用仅需20 mmol L−1乙醇。乙醇和乙醛通过抑制神经类固醇合成和阻断N -甲基- D -天冬氨酸受体（NMDAR）来克服对神经类固醇染色和LTP的影响。结论海马体内局部乙醇代谢产生的乙醛是锥体神经元合成神经类固醇的信号，参与了重度酒精中毒相关的突触功能障碍。
AimAs severe alcohol intoxication impairs memory function, a high concentration of ethanol (60 mmol L−1) acutely inhibits long‐term potentiation (LTP), a cellular model of learning and memory, in rat hippocampal slices. Neurosteroids are involved in this LTP inhibition. We recently reported that the inhibitory effects of 60 mmol L−1ethanol are blocked by 4‐methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that acetaldehyde locally generated within the hippocampus participates in LTP inhibition. We investigated whether acetaldehyde generated by ethanol metabolism contributes to neurosteroidogenesis and LTP inhibition.ResultsLike 60 mmol L−1ethanol, we found that exogenous acetaldehyde enhanced neurosteroid immunostaining in CA1 pyramidal neurons, and that augmented neurosteroid immunostaining by high ethanol alone was blocked by 4MP, but not by inhibitors of other ethanol metabolism pathways. The inhibitory effects of 60 mmol L−1ethanol on LTP were mimicked by a lower concentration of ethanol (20 mmol L−1) plus acetaldehyde (60 μmol L−1), although neither agent alone was effective at these concentrations, suggesting that 60 mmol L−1ethanol inhibits LTP through multiple actions, one of which involves acetaldehyde and the other of which requires just 20 mmol L−1ethanol. The effects of ethanol and acetaldehyde on neurosteroid staining and LTP were overcome by inhibition of neurosteroid synthesis and by blockade of N‐methyl‐D‐aspartate receptors (NMDAR).ConclusionThese observations show that acetaldehyde generated by local ethanol metabolism within the hippocampus serves as a signal for neurosteroid synthesis in pyramidal neurons, and participates in the synaptic dysfunction associated with severe alcohol intoxication.