Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder.
Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder.
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DOI：
10.1016/j.jpsychires.2010.03.013
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发表时间：
2010-11
影响因子：
4.8
通讯作者：
Shigeto Yamamoto;S. Morinobu;Y. Iwamoto;Y. Ueda;S. Takei;Yosuke Fujita;S. Yamawaki
中科院分区：
文献类型：
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作者：
Shigeto Yamamoto;S. Morinobu;Y. Iwamoto;Y. Ueda;S. Takei;Yosuke Fujita;S. Yamawaki
以往的研究表明，大鼠受到单一的长期压力（SPS）表现出创伤后应激障碍（PTSD）样症状，如增强的背景恐惧，以响应创伤相关和创伤无关的事件。此外，我们以前报道，上调海马甘氨酸转运蛋白1（GlyT-1）mRNA的背景暴露后可能是受损的恐惧消退SPS大鼠的初始机制。为了阐明海马甘氨酸能系统参与SPS大鼠的恐惧消退受损，我们测量了冷冻持续时间和海马Gly-T1 mRNA水平的变化的时间过程，使用上下文恐惧条件反射（FC）和消退训练。我们还使用体内微透析来测量在FC和第一次上下文曝光之间的时间间隔期间海马中细胞外甘氨酸的浓度。SPS大鼠表现出增加和持续的上下文恐惧反应。SPS大鼠增强的背景恐惧反应与FC后海马Gly-T1 mRNA水平相对于假手术大鼠的持续增加相关，并与细胞外甘氨酸浓度的降低相关。GlyT-1 mRNA水平在大鼠进行了反复的灭绝训练显着低于大鼠没有进行灭绝训练。这些研究结果表明，海马甘氨酸能系统的活动减少可能密切参与受损的恐惧消退在SPS大鼠，这表明甘氨酸能系统的激活d-环丝氨酸或GlyT-1抑制剂可能会改善恐惧消退的损害。
Previous studies have demonstrated that rats subjected to single prolonged stress (SPS) exhibit posttraumatic stress disorder (PTSD)-like symptoms, such as enhanced contextual fear in response to trauma-related and trauma-unrelated events. Furthermore, we previously reported that upregulation of hippocampal glycine transporter 1 (GlyT-1) mRNA after context exposure could be the initial mechanism underlying impaired fear extinction in SPS rats. To clarify the involvement of the hippocampal glycinergic system in impaired fear extinction in SPS rats, we measured the time course of changes in the duration of freezing and the hippocampal levels of Gly-T1 mRNA using contextual fear conditioning (FC) and extinction training. We also used in vivo microdialysis to measure the concentration of extracellular glycine in the hippocampus during the time interval between FC and the first context exposure. SPS rats exhibited increased and sustained contextual fear responses. The enhanced contextual fear response in SPS rats was associated with a sustained increase in hippocampal levels of Gly-T1 mRNA after FC relative to sham rats, and by a decrease in the extracellular glycine concentration. GlyT-1 mRNA levels in rats that underwent repeated extinction training were significantly lower than in rats that did not undergo extinction training. These findings indicate that reduced activity of the hippocampal glycinergic system could be closely involved in impaired fear extinction in SPS rats, suggesting that activation of the glycinergic system by d-cycloserine or GlyT-1 inhibitors may ameliorate the impairment of fear extinction.