Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri (Y.I., S.J.M., C.F.Z.); and Sage Therapeutics, Cambridge, Massachusetts (J.J.D.).
Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri (Y.I., S.J.M., C.F.Z.); and Sage Therapeutics, Cambridge, Massachusetts (J.J.D.)
J Pharmacol Exp Ther. 2021 Apr;377(1):181-188. doi: 10.1124/jpet.120.000376. Epub 2021 Jan 13.
Ethanol is a noncompetitive inhibitor of -methyl-d-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo. We found that 24S-hydroxycholesterol and a synthetic oxysterol analog, SGE-301, overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent effects of ethanol on LTP in vitro, and the synthetic analog reversed defects in one-trial inhibitory avoidance learning in vivo. These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMS may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition. SIGNIFICANCE STATEMENT: Ethanol acutely inhibits hippocampal NMDARs, LTP, and learning. This study found that certain oxysterols that are NMDAR-positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP, and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses.
乙醇是 N-甲基-D-天冬氨酸受体（NMDARs）的非竞争性抑制剂，可急性破坏海马突触可塑性和学习。在本研究中，我们研究了 NMDAR 的氧化固醇正变构调节剂（PAMs）对乙醇介导的 NMDAR 抑制、阻断长时程增强（LTP）和长时程抑制（LTD）以及体内单次学习缺陷的影响。我们发现 24S-羟基胆固醇和合成氧化固醇类似物 SGE-301 克服了乙醇对 CA1 区 NMDAR 介导的突触反应的影响，但并未改变乙醇对 LTD 的急性作用；然而，合成氧化固醇克服了 LTP 的急性抑制作用。此外，两种氧化固醇都克服了乙醇对 LTP 的体外持续作用，并且合成类似物逆转了体内单次抑制性回避学习的缺陷。这些结果表明，乙醇对 LTP 和 LTD 的影响是通过 NMDAR 拮抗以外的复杂机制产生的，而氧化固醇 NMDAR PAMs 可能代表预防和逆转急性乙醇介导的认知变化的新方法。意义：乙醇急性抑制海马 NMDAR、LTP 和学习。本研究发现，某些作为 NMDAR 正变构调节剂的氧化固醇可以克服乙醇对 NMDAR、LTP 和学习的急性作用。氧化固醇的作用与抑制整合细胞应激反应的药物不同。
