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bioRxiv · 10.64898/2025.12.21.695760

The atypical antidepressant and cognitive enhancer tianeptine disinhibits hippocampal CA1 pyramidal neurons by reducing GABAergic neurotransmission

Martin, S. J.·Li, Y.·Tench, B.·Phillips, G. D.·Lambert, J. J.·Belelli, D.
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Abstract

Tianeptine is an atypical antidepressant and cognitive enhancer whose actions are thought to be dependent on the activation of opioid receptors, including {micro}-opioid receptors expressed on hippocampal interneurons. Agonists of these receptors can cause a disinhibition of principal neurons by inhibiting GABA release or interneuron firing. However, direct evidence for a similar action of tianeptine has not previously been reported. We therefore studied the effects of tianeptine on in vivo and in vitro measures of inhibitory synaptic transmission. CA1 field excitatory postsynaptic potentials (fEPSPs) and local field potential (LFP) activity were recorded in area CA1 of anaesthetised rats. To obtain a more direct measure of tianeptines actions on GABA release, we also conducted whole-cell patch-clamp recordings of spontaneous and evoked inhibitory postsynaptic potentials (sIPSCs and eIPSCs) in CA1 pyramidal neurons in vitro. Intrahippocampal infusion of tianeptine (15 mM; 1 {micro}l) caused a marked reduction in paired-pulse inhibition (PPI) of the population spike (20-ms inter-stimulus interval) elicited in the CA1 cell-body layer. Separate recordings in the stratum radiatum revealed an enhancement of beta and gamma-frequency LFP activity, an effect of tianeptine that we have reported previously. Infusion of the GABAA receptor antagonist bicuculline caused a similar reduction in PPI but did not induce beta/gamma oscillations. In mouse hippocampal slices, tianeptine (50 {micro}M) reduced both sIPSC frequency and eIPSC amplitude. These results confirm that tianeptine causes a disinhibition of CA1 pyramidal cells, but suggest that a simple blockade of GABAergic transmission is not alone sufficient to explain tianeptines effects on hippocampal network activity.

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Martin, S. J., Li, Y., Tench, B., Phillips, G. D., Lambert, J. J., Belelli, D.. 2025-12-23. The atypical antidepressant and cognitive enhancer tianeptine disinhibits hippocampal CA1 pyramidal neurons by reducing GABAergic neurotransmission. https://doi.org/10.64898/2025.12.21.695760

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