Kole Maarten H P, Swan Laura, Fuchs Eberhard
Division of Neurobiology, German Primate Center, Göttingen, Germany. mhpkoledpz.gwdg.de
Eur J Neurosci. 2002 Sep;16(5):807-16. doi: 10.1046/j.1460-9568.2002.02136.x.
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.
近期关于抗抑郁药作用的假说表明其对兴奋性氨基酸传递具有调节作用。在此，我们采用全细胞膜片钳技术，研究了长期应用抗抑郁药噻奈普汀对大鼠海马CA3连合-联合（c/a）谷氨酸受体离子通道的影响。通过将大鼠每日束缚应激三周并联合噻奈普汀治疗（10毫克/千克/天）来测试该药物的作用。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（EPSC）的失活时间常数和幅度，但不影响α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人藻酸受体介导的EPSC。用噻奈普汀对受应激动物进行联合药物治疗，可使NMDA受体与AMPA/海人藻酸受体介导电流的幅度比恢复正常，并防止应激诱导的NMDA-EPSC失活减弱。双脉冲易化和频率依赖性可塑性均保持不变。然而，在对照动物和受应激动物中，噻奈普汀治疗均增强了EPSC输入-输出关系的斜率。后者可通过在体外将海马脑片暴露于10微摩尔的噻奈普汀来模拟，这迅速增加了NMDA-和AMPA/海人藻酸EPSC的幅度。EPSC的增强可被细胞内存在的激酶抑制剂星形孢菌素（1微摩尔）阻断，这表明在CA3 c/a突触处涉及突触后磷酸化级联反应而非突触前释放机制。这些结果表明，噻奈普汀作用于CA3 c/a突触处谷氨酸受体的磷酸化状态。噻奈普汀这种新的信号转导机制可能为其神经保护特性提供一种机制解释，此外，还为其记忆增强和/或抗抑郁活性提供一条药理学途径。
