The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats
The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats
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DOI：
10.1046/j.1460-9568.2002.02136.x
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发表时间：
2002-09-01
影响因子：
3.4
通讯作者：
Fuchs, E
中科院分区：
文献类型：
--
作者：
Kole, MHP;Swan, L;Fuchs, E
最近关于抗抑郁药作用的假设暗示了对兴奋性氨基酸传递的调节。本研究采用全细胞膜片钳技术，对大鼠海马CA3谷氨酸受体离子通道（c/a）长期应用天奈汀抗抑郁药的影响进行了研究。通过将大鼠与天奈肽（10mg /kg/天）联合给予三周的每日约束应激来测试药物的影响。虽然应激增加了N -甲基-d-天冬氨酸（NMDA）受体介导的兴奋性突触后电流（EPSCs）的失活时间常数和振幅，但对α -氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)/盐酸盐受体介导的EPSCs没有影响。与天奈汀同时给应激动物进行药物治疗，导致NMDA受体与AMPA/kainate受体介导电流的振幅比呈标准化缩放，并阻止了应激诱导的NMDA- epscs失活的衰减。配对脉冲促进和频率相关的可塑性保持不变。然而，在对照组和应激动物中，天奈肽处理增强了EPSCs投入产出关系的斜率。后者通过在离体海马切片中暴露10 mg天奈肽来模拟，可迅速增加NMDA-和AMPA/kainate EPSCs的振幅。EPSCs的增强可被细胞内存在的激酶抑制剂staurosporine阻断（1 mum），这表明在CA3 c/a突触中参与突触后磷酸化级联而不是突触前释放机制。这些结果表明，天奈肽靶向ca3c /a突触谷氨酸受体的磷酸化状态。这一新的天奈肽信号转导机制可能为其神经保护特性提供了机制解析，此外，还为其增强记忆和/或抗抑郁活性提供了药理学轨迹。
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 mum 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 mum), 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.