GABAergic neurosteroids mediate the effects of ethanol on long-term potentiation in rat hippocampal slices
GABAergic neurosteroids mediate the effects of ethanol on long-term potentiation in rat hippocampal slices
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DOI：
10.1111/j.1460-9568.2007.05809.x
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发表时间：
2007-10-01
影响因子：
3.4
通讯作者：
Zorumski, Charles F.
中科院分区：
文献类型：
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作者：
Izumi, Yukitoshi;Murayama, Kenki;Zorumski, Charles F.
我们之前发现乙醇对海马突触可塑性具有复杂的影响，通过不同机制抑制长时程增强（LTP）和长时程抑制。长期抑郁的阻断似乎是通过对 N-甲基-D-天冬氨酸受体的作用介导的，而 LTP 的阻断涉及通过 γ-氨基丁酸-A 受体 (GABA(A)Rs) 的增强抑制。为了探究影响 LTP 的因素，我们检测了不同浓度的乙醇阻断大鼠海马切片 CA1 区 LTP 的能力。完整的 LTP 封闭需要 60 mM 乙醇。在 (3 α 5 α)-3-羟基孕烷-20-酮（一种 GABA(A)R 增强神经类固醇）存在下，LTP 阻滞在较低乙醇浓度下增强，表明神经类固醇可能是乙醇对 LTP 作用的重要贡献者。 Consistent with this, we found that block of LTP by 60 mM ethanol was overcome by coadministration of a cyclodextrin that binds and removes lipophilic neurosteroids.更具体地说，用非那雄胺（一种抑制 5α 还原神经类固醇合成的药物）或用抑制 5α 还原神经类固醇对 GABA(A)R 的作用的药物处理切片克服了 60 mM 乙醇对 LTP 的影响。总而言之，这些结果表明 GABA(A)R 增强神经类固醇的快速产生在介导乙醇对 LTP 的影响中发挥着关键作用。
We previously found that ethanol has complex effects on hippocampal synaptic plasticity, inhibiting long-term potentiation (LTP) and long-term depression by different mechanisms. The block of long-term depression appears to be mediated by effects on N-methyl-D-aspartate receptors, whereas the block of LTP involves augmented inhibition via gamma-aminobutyric acid-A receptors (GABA(A)Rs). To pursue factors contributing to effects on LTP, we examined the ability of various concentrations of ethanol to block LTP in the CA1 region of rat hippocampal slices. Complete LTP block required 60 mM ethanol. LTP block was enhanced at lower ethanol concentrations in the presence of (3 alpha 5 alpha)-3-hydroxypregnan-20-one, a GABA(A)R-potentiating neurosteroid, suggesting that neurosteroids may be important contributors to the effects of ethanol on LTP. Consistent with this, we found that block of LTP by 60 mM ethanol was overcome by coadministration of a cyclodextrin that binds and removes lipophilic neurosteroids. More specifically, treatment of slices with finasteride, an agent that inhibits the synthesis of 5 alpha-reduced neurosteroids, or with an agent that inhibits the effects of 5 alpha-reduced neurosteroids on GABA(A)Rs overcame the effects of 60 mM ethanol on LTP. Taken together, these results indicate that acute production of GABA(A)R-enhancing neurosteroids plays a key role in mediating the effects of ethanol on LTP.