Ketamine promotes rapid and transient activation of AMPA receptor-mediated synaptic transmission in the dorsal raphe nucleus

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 88; pp. 243 - 252
• Main Authors: Llamosas, Nerea, Perez-Caballero, Laura, Berrocoso, Esther, Bruzos-Cidon, Cristina, Ugedo, Luisa, Torrecilla, Maria
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 10.01.2019
• Subjects: Animals; Dorsal Raphe Nucleus - drug effects; Dorsal Raphe Nucleus - metabolism; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists - pharmacology; GABA Antagonists - pharmacology; Hindlimb Suspension; Immobility Response, Tonic - drug effects; Indoles - pharmacokinetics; Ketamine - pharmacology; Male; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Phosphorylation - drug effects; Picrotoxin - pharmacology; Purines - pharmacokinetics; Receptors, AMPA - metabolism; Signal Transduction - drug effects; Synaptic Transmission - drug effects; TOR Serine-Threonine Kinases - metabolism; DMSO; sEPSCs; ACSF; PFC; p-mTOR; D-AP5; DR; sIPSCs; DNQX; MK-801; TST; mTOR; eEPSCs; PP242; PSD-95
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2018.07.022

Accumulating evidence indicates that the antidepressant effects of ketamine are, in part, mediated by an increase in the AMPA receptor-mediated neurotransmission in depression related areas, such as the prefrontal cortex (PFC). Therefore, activity in PFC-projecting areas related to major depression, such as the dorsal raphe nucleus (DR), may also be modulated by ketamine. We used whole-cell patch-clamp recordings and western blot experiments to determine whether ketamine promotes acute and maintained alterations in glutamatergic transmission and mTOR pathway in the DR. Bath perfusion of ketamine, but not the NMDA receptor antagonist D-AP5, increased the frequency of AMPA receptor-mediated spontaneous EPSCs (sEPSCs) in DR neurons. However, ketamine did not affect evoked EPSCs or spontaneous inhibitory currents (sIPSCs). Pre-incubation of DR slices with the mTOR inhibitor PP242 decreased the frequency of sEPSCs and prevented the effect of ketamine. The results also show that while no electrophysiological effects were detected 24 h after ketamine administration, phosphorylation levels of mTOR were significantly increased in the DR. Nevertheless, expression levels of synaptic proteins were unaffected at that time. Altogether, the present data demonstrate that ketamine transiently increases spontaneous AMPA receptor-mediated neurotransmission in the DR. •Ketamine increases spontaneous glutamate release from presynaptic terminals in the dorsal raphe (DR) nucleus, which activates spontaneous AMPA receptor-mediated synaptic activity•mTOR inhibition reduces spontaneous AMPA activity and prevents ketamine's effect.•Ketamine increases p-mTOR 24 h after administration (30 mg kg-1), but does not affect synaptic protein levels.•Sustained effects of ketamine in the DR are only appreciable at the biochemical level since no electrophysiological effects are observed 24 h after systemic injection.