The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / pharmacology*
  • Corticosterone / blood
  • Electrophysiology
  • Hippocampus / drug effects*
  • Male
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Receptors, AMPA / drug effects
  • Receptors, Glutamate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Restraint, Physical
  • Signal Transduction
  • Stress, Psychological* / drug therapy
  • Stress, Psychological* / metabolism
  • Synaptic Transmission* / drug effects
  • Thiazepines / pharmacology*


  • Antidepressive Agents, Tricyclic
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Thiazepines
  • tianeptine
  • Corticosterone