The atypical antidepressant tianeptine causes opioid-receptor-dependent beta oscillations in the rat hippocampus

TY - JOUR

T1 - The atypical antidepressant tianeptine causes opioid-receptor-dependent beta oscillations in the rat hippocampus

AU - Burt, Scott G.

AU - Phillips, Grant D.

AU - Lambert, Jeremy J.

AU - Martin, Stephen J.

N1 - © 2026 The Authors.

PY - 2026/4/7

Y1 - 2026/4/7

N2 - Tianeptine is an atypical antidepressant and cognitive enhancer. Previous research indicates that its antidepressant-like efficacy in animals depends on the phosphorylation of GluA1-subunit-containing AMPA receptors (AMPARs), and the activation of μ-opioid receptors on hippocampal interneurons. Both actions might alter synaptic strength and network activity; we therefore studied the effects of tianeptine on evoked synaptic responses and local-field-potential (LFP) oscillations in area CA1 of male urethane-anaesthetised rats. Electrodes were implanted to record CA1 LFP and field excitatory postsynaptic potentials (fEPSPs) elicited by stimulation of CA3. A temperature probe was implanted in the contralateral hippocampus. Subcutaneous injection of tianeptine (10 & 30 mg/kg) caused a dose-dependent increase in hippocampal beta-frequency activity and a modest increase in fEPSP slope that were blocked by the opioid-receptor antagonist naloxone. Injection of the opioid buprenorphine (0.03 mg/kg) had similar effects, but ketamine (10 mg/kg), another atypical antidepressant, caused a distinct pattern of LFP changes characterised by a naloxone-insensitive increase in slow-gamma activity. Injection of 30 mg/kg tianeptine and 0.03 mg/kg buprenorphine was associated with an increase in brain temperature of ∼0.6 °C, sufficient to fully explain the increase in fEPSP slope, but not the increase in LFP activity. Injection of tianeptine also caused a reduction in the amplitude of the inhibitory ‘tail’ of the fEPSP, consistent with a blockade of feedforward inhibition. These results indicate that tianeptine, like several other atypical antidepressant drugs, enhances hippocampal beta/gamma-frequency LFP activity. This action is dependent on opioid-receptor activation and may depend on the disinhibition of principal neurons, a possibility that we are exploring.

AB - Tianeptine is an atypical antidepressant and cognitive enhancer. Previous research indicates that its antidepressant-like efficacy in animals depends on the phosphorylation of GluA1-subunit-containing AMPA receptors (AMPARs), and the activation of μ-opioid receptors on hippocampal interneurons. Both actions might alter synaptic strength and network activity; we therefore studied the effects of tianeptine on evoked synaptic responses and local-field-potential (LFP) oscillations in area CA1 of male urethane-anaesthetised rats. Electrodes were implanted to record CA1 LFP and field excitatory postsynaptic potentials (fEPSPs) elicited by stimulation of CA3. A temperature probe was implanted in the contralateral hippocampus. Subcutaneous injection of tianeptine (10 & 30 mg/kg) caused a dose-dependent increase in hippocampal beta-frequency activity and a modest increase in fEPSP slope that were blocked by the opioid-receptor antagonist naloxone. Injection of the opioid buprenorphine (0.03 mg/kg) had similar effects, but ketamine (10 mg/kg), another atypical antidepressant, caused a distinct pattern of LFP changes characterised by a naloxone-insensitive increase in slow-gamma activity. Injection of 30 mg/kg tianeptine and 0.03 mg/kg buprenorphine was associated with an increase in brain temperature of ∼0.6 °C, sufficient to fully explain the increase in fEPSP slope, but not the increase in LFP activity. Injection of tianeptine also caused a reduction in the amplitude of the inhibitory ‘tail’ of the fEPSP, consistent with a blockade of feedforward inhibition. These results indicate that tianeptine, like several other atypical antidepressant drugs, enhances hippocampal beta/gamma-frequency LFP activity. This action is dependent on opioid-receptor activation and may depend on the disinhibition of principal neurons, a possibility that we are exploring.

KW - Local-field potential

KW - CA1

KW - ketamine

KW - buprenorphine

KW - naloxone

KW - urethane

KW - gamma

U2 - 10.1016/j.neuropharm.2026.110953

DO - 10.1016/j.neuropharm.2026.110953

M3 - Article

C2 - 41956239

SN - 0028-3908

VL - 294

JO - Neuropharmacology

JF - Neuropharmacology

M1 - 110953

ER -