Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABAA receptor.
Glòria Salort, María Álvaro-Bartolomé, Jesús A García-Sevilla
Progress in Neuro-Psychopharmacology and Biological Psychiatry July 10, 2018 DOI: 10.1016/j.pnpbp.2018.07.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mouse brain cortex |
| Interventions | Ketamine Flumazenil SL-327 |
| Dose | 5, 15, and 150 mg/kg ketamine |
| Duration | Up to 50 min of ketamine-induced sleep |
| Measures | Western immunoblot |
| Topics | Ketamine Neuroplasticity Esketamine |
| Keywords | Cerebral cortex Animals Mice Flumazenil Receptors, gaba-a Nerve tissue proteins Gaba modulators Analgesics Enzyme inhibitors Immobility response, tonic Neuronal plasticity Dose-response relationship, drug Time factors Male Reflex, righting Fadd Nf-kb Hypnosis Mouse brain Mek-erk |
| Key findings | Ketamine at hypnotic (150 mg/kg) and subhypnotic (5-15 mg/kg) doses uncoupled MEK from ERK signaling in mouse cortex, increasing p-MEK (up to 79%) while decreasing p-ERK (up to 46%), and raised p-FADD dose-dependently. Flumazenil prolonged ketamine sleep and blocked p-MEK upregulation, and the MEK inhibitor SL-327 prolonged sleep, suggesting reduced p-ERK contributes to ketamine hypnosis. |
Abstract
Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET-induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p-FADD and other neuroplastic markers in brain. Low (5-15 mg/kg) and high (150 mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex. During the time course of KET (150 mg/kg)-induced sleep (up to 50 min) p-MEK was increased (up to +79%) and p-ERK decreased (up to -46%) indicating disruption of MEK to ERK signal. Subhypnotic KET (5-15 mg/kg) also revealed uncoupling of p-MEK (+13-81%) to p-ERK (unchanged content). KET did not alter contraregulatory MAPK mechanisms such as inactivated p-MEK1 (ERK dampening) and phosphatases MKP1/2/3 (ERK dephosphorylation). As other relevant findings, KET (5, 15 and 150 mg/kg) upregulated p-FADD in a dose-dependent manner, and for the hypnotic dose the effect paralleled the time course of sleep which resulted in increased p-FADD/FADD ratios. KET (150 mg/kg) also increased NF-κΒ and PSD-95 neuroplastic markers. Flumazenil (a neutral allosteric antagonist at GABAA receptor) prolonged KET sleep and blocked p-MEK upregulation, indicating the involvement of this receptor as a negative modulator. SL-327 (a MEK inhibitor) augmented KET sleep, further indicating the relevance of reduced p-ERK1/2 in KET-induced hypnosis. These findings suggest that hypnotic and subhypnotic doses of KET inducing uncoupling of p-MEK to p-ERK signal and regulation of p-ERK (downregulation) and p-FADD (upregulation) may participate in the expression of some of its adverse effects (e.g. amnesia, dissociative effects).
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Citations in the library
Cited by 6
- Effects of subanesthetic intravenous ketamine infusion on neuroplasticity-related proteins in the prefrontal cortex, amygdala, and hippocampus of Sprague-Dawley rats IBRO Reports January 16, 2019
- Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review Frontiers in Psychiatry June 26, 2023
- Ketamine enhances histone H3 (Ser10) phosphorylation via JNK signaling and multi-omics profiling of the hippocampus in a psychotic-like mouse model. Behavioral and Brain Functions June 25, 2026
- Ketamine reduces electrophysiological network activity in cortical neuron cultures already at sub-micromolar concentrations - Impact on TrkB-ERK1/2 signaling. Neuropharmacology May 15, 2023
- Implications on hypnotherapy: Neuroplasticity, epigenetics and pain. Neuroscience & Biobehavioral Reviews December 2021
and 1 more in the library
Cites 7
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- NMDA Antagonist Neurotoxicity: Mechanism and Prevention Science December 6, 1991
- Ketamine Anesthesia & Analgesia November 1, 1998
and 2 more in the library