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

M H P Kole*, L Swan, E Fuchs

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    162 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)807-816
    Number of pages10
    JournalEuropean Journal of Neuroscience
    Volume16
    Issue number5
    DOIs
    Publication statusPublished - Sep-2002

    Keywords

    • AMPA
    • EPSC
    • hippocampus
    • NMDA
    • phosphorylation
    • tianeptine
    • METHYL-D-ASPARTATE
    • MEDIATED GENE-TRANSCRIPTION
    • LONG-TERM POTENTIATION
    • MESSENGER-RNA LEVELS
    • PYRAMIDAL CELLS
    • TRICYCLIC ANTIDEPRESSANTS
    • PROTEIN-KINASE
    • MICE LACKING
    • PLASTICITY
    • DEPRESSION

    Cite this