(2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism
| Autor: | Todd D. Gould, Lace M. Riggs, Edson X. Albuquerque, Scott M. Thompson, Jonathan Fischell, Panos Zanos, Edna F. R. Pereira, Yasco Aracava |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Presynaptic Terminals Glutamic Acid AMPA receptor Neurotransmission Hippocampus Synaptic Transmission Article Rats Sprague-Dawley 03 medical and health sciences Glutamatergic 0302 clinical medicine Organ Culture Techniques medicine Animals Pharmacology Chemistry Glutamate receptor Excitatory Postsynaptic Potentials Long-term potentiation 030227 psychiatry Rats Psychiatry and Mental health medicine.anatomical_structure Schaffer collateral embryonic structures Synapses Excitatory postsynaptic potential NMDA receptor Female Ketamine Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neuropsychopharmacology |
| ISSN: | 1740-634X |
| Popis: | Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its dissociative-like properties and abuse potential. While (2R,6R)-HNK is thought to exert its antidepressant-like effects by potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission, it is unknown how it exerts this effect. The acute synaptic effects of (2R,6R)-HNK were examined by recording field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) in rat hippocampal slices. (2R,6R)-HNK bath application caused a rapid and persistent potentiation of AMPAR-mediated Schaffer collateral (SC)-CA1 fEPSPs in slices derived from male and female rats. The (2R,6R)-HNK-induced potentiation occurred independent of N-methyl-D-aspartate receptor (NMDAR) activity, was accompanied by a concentration-dependent decrease in paired pulse ratios, and was occluded by raising glutamate release probability. In additon, in the presence of tetrodotoxin, (2R,6R)-HNK increased the frequency, but not amplitude, of mEPSC events, confirming a presynaptic site of action that is independent of glutamatergic network disinhibition. A dual extracellular recording configuration revealed that the presynaptic effects of (2R,6R)-HNK were synapse-selective, occurring in CA1-projecting SC terminals, but not in CA1-projecting temporoammonic terminals. Overall, we found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration-dependent, NMDAR-independent, and synapse-selective increase in glutamate release probability with no direct actions on AMPAR function. These findings provide novel insight regarding (2R,6R)-HNK's acute mechanism of action, and may inform novel antidepressant drug mechanisms that could yield superior efficacy, safety, and tolerability. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink