Clinically relevant concentrations of ketamine mainly affect long-term potentiation rather than basal excitatory synaptic transmission and do not change paired-pulse facilitation in mouse hippocampal slices

Ribeiro, Patrícia; Tomé, Ângelo R.; Silva, Henrique B.; Cunha, Rodrigo A.; Antunes, Luís

doi:10.1016/j.brainres.2014.03.004

Cited by 29 publications

(19 citation statements)

References 42 publications

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“…Several reports have demonstrated that ketamine, and also (2R,6R)-HNK, applied in the perfusion solution enhance AMPARmediated synaptic transmission in the hippocampus. 6,20,38,[54][55][56][57][58] Other reports demonstrate a lack of effect of this treatment in the Ketamine alters mesolimbic synaptic plasticity N Yao et al same brain region 59 and suggest that the acute effect of ketamine is dependent on the concentration of this compound used and the location of the recording within the hippocampus (somatic vs dendritic recordings). 58 The ketamine-induced increase in hippocampal synaptic transmission is mimicked or blocked by NMDAR antagonists 55,57,58 and requires presynaptic NMDARs.…”

Section: Discussionmentioning

confidence: 99%

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

et al. 2017

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Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive. We found that one day after the injection of a low dose of ketamine, long-term potentiation (LTP) in the nucleus accumbens (NAc) was impaired. Loss of LTP was maintained for 7 days and was not associated with an altered basal synaptic transmission mediated by AMPARs and N-methyl-D-aspartate receptors (NMDARs). Inhibition of mammalian target of rapamycin signaling with rapamycin did not prevent the ketamine-induced loss of LTP but inhibited LTP in saline-treated mice. However, ketamine blunted the increase in the phosphorylation of the GluA1 subunit of AMPARs at a calcium/calmodulin-dependent protein kinase II/protein kinase C site induced by an LTP induction protocol. Moreover, ketamine caused a persistent increased phosphorylation of GluA1 at a protein kinase A site. (2R,6R)-HNK also impaired LTP in the NAc. In dopaminergic neurons of the ventral tegmental area from ketamine-or (2R,6R)-HNK-treated mice, AMPAR-mediated responses were depressed, while those mediated by NMDARs were unaltered, which resulted in a reduced AMPA/NMDA ratio, a measure of long-term synaptic depression. These results demonstrate that a single injection of ketamine or (2R,6R)-HNK induces enduring alterations in the function of AMPARs and synaptic plasticity in brain regions involved in reward-related behaviors.

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Section: Discussionmentioning

confidence: 99%

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

et al. 2017

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“…LTD inhibition and enhancement of somatic EPSPs occurred shortly after ketamine administration, whereas modulation of LTP occurred after 2 hours or later. Clinically relevant micromolar concentrations of ketamine dose dependently decreased LTP without affecting paired-pulsed facilitation in Schaffer collateral-CA1 pyramidal neuron synapses in a mouse HC slice preparation, but higher concentrations affected basal excitatory synaptic transmission and presynaptic volley amplitude (Ribeiro et al, 2014). In a model for psychosis, administrations of ketamine (20 mg/kg s.c. given six times, once every 2 hours.)…”

Section: F N-methyl-d-aspartate Receptor Antagonistsmentioning

confidence: 98%

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

Korpi¹,

Hollander²,

Farooq

et al. 2015

Pharmacol Rev

129

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“…In addition, the concentrations of ketamine are different in different tissues. During anesthesia, ketamine preferentially accumulates in the brain, and its concentration present in the brain is considerably higher than its plasma concentration [31,32]. Moreover, 25 µmol/L ketamine has significantly inhibited hHCN currents (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node

et al. 2017

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Aims: To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN). Methods: The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart. Results: Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC₅₀ of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner. Conclusion: Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine.

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Clinically relevant concentrations of ketamine mainly affect long-term potentiation rather than basal excitatory synaptic transmission and do not change paired-pulse facilitation in mouse hippocampal slices

Cited by 29 publications

References 42 publications

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node

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