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首页> 外文期刊>The European Journal of Neuroscience >The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats.
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The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats.

机译:抗抑郁药噻庚啶可持续调节慢性应激大鼠海马CA3连合缔合突触的谷氨酸受体电流。

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摘要

Recent hypotheses on the action of antidepressants imply a modulation of excitatory amino acid transmission. Here, the effects of long-term antidepressant application in rats with the drug tianeptine were examined at hippocampal CA3 commissural associational (c/a) glutamate receptor ion channels, employing the whole-cell patch-clamp technique. The drug's impact was tested by subjecting rats to daily restraint stress for three weeks in combination with tianeptine treatment (10 mg/kg/day). Whereas stress increased the deactivation time-constant and amplitude of the N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs), it did not affect the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor-mediated EPSCs. Concomitant pharmacological treatment of stressed animals with tianeptine resulted in a normalized scaling of the amplitude ratio of NMDA receptor to AMPA/kainate receptor-mediated currents and prevented the stress-induced attenuation of NMDA-EPSCs deactivation. Both paired-pulse-facilitation and frequency-dependent plasticity remained unchanged. Both in control and stressed animals, however, tianeptine treatment strengthened the slope of the input-output relation of EPSCs. The latter was mimicked by exposing hippocampal slices in vitro with 10 micro m tianeptine, which rapidly increased the amplitudes of NMDA- and AMPA/kainate EPSCs. The enhancement of EPSCs could be blocked by the intracellular presence of the kinase inhibitor staurosporine (1 micro m), suggesting the involvement of a postsynaptic phosphorylation cascade rather then presynaptic release mechanisms at CA3 c/a synapses. These results indicate that tianeptine targets the phosphorylation-state of glutamate receptors at the CA3 c/a synapse. This novel signal transduction mechanism for tianeptine may provide a mechanistic resolution for its neuroprotective properties and, moreover, a pharmacological trajectory for its memory enhancing and/or antidepressant activity.
机译:关于抗抑郁药作用的最新假说暗示了兴奋性氨基酸传递的调节。在这里,使用全细胞膜片钳技术在海马CA3连合相关(c / a)谷氨酸受体离子通道上检查了长期使用抗抑郁药使用替尼汀的大鼠的作用。通过将大鼠每日束缚压力与三肽合用(10 mg / kg /天)进行三周的测试,测试了这种药物的作用。尽管应力增加了N-甲基-d-天冬氨酸(NMDA)受体介导的兴奋性突触后电流(EPSC)的失活时间常数和幅度,但它并不影响α-氨基-3-羟基-5-甲基-4丙酸异异唑酯(AMPA)/海藻酸酯受体介导的EPSC。替尼汀对应激动物的药理学治疗导致NMDA受体与AMPA /海藻酸酯受体介导的电流振幅比的标准化缩放,并防止了应力诱导的NMDA-EPSCs失活衰减。成对脉冲促进和频率依赖性可塑性均保持不变。然而,无论是在对照动物还是应激动物中,天肽治疗都增强了EPSC投入-产出关系的斜率。后者是通过在体外用10微米m的替丁汀暴露海马切片来模仿的,后者迅速增加了NMDA和AMPA /海藻酸酯EPSC的幅度。 EPSC的增强可能被激酶抑制剂星形孢菌素(1微米)的细胞内存在所阻断,表明突触后磷酸化级联的参与而不是在CA3 c / a突触中的突触前释放机制。这些结果表明,天肽可靶向CA3 c / a突触处谷氨酸受体的磷酸化状态。替丁汀的这种新颖的信号转导机制可为其神经保护特性提供机理解析,并且为其记忆增强和/或抗抑郁活性提供药理学轨迹。

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