Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: An <i>in vivo</i> electrophysiological study on monoaminergic and glutamatergic neurons

Iskandrani, Kareem S El; Oosterhof, Chris; Mansari, Mostafa El; Blier, Pierre

doi:10.1177/0269881115573809

Cited by 58 publications

(62 citation statements)

References 53 publications

(79 reference statements)

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“…The increased climbing behavior induced by ketamine could be related to the ability of NMDAR antagonists to increase dopaminergic activity in the striatum and NAc (Lai et al, 2014;El Iskandrani et al, 2015). A blockade of NMDARs located on GABA interneurons, when exerted by MK-801, phencyclidine, and ketamine, decreases GABAergic inhibition (Littlewood et al, 2006;Sakamoto et al, 2006;Homayoun and Moghaddam, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the subchronic administration of MK-801, an NMDA antagonist, induced a decrease in the expression of the mRNA of 5-HT6Rs in the striatum (Healy and Meador-Woodruff, 1999). Moreover, the continuous administration of ketamine resulted in an AMPA-dependent increase in dopaminergic activity (El Iskandrani et al, 2015). Although these findings are not sufficient to explain the aforementioned observation, they point out the necessity of analyzing the role of dose to explain these different outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Briones-Aranda

Suárez-Santiago

Picazo

et al. 2016

Behavioural Pharmacology

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Some types of schizophrenia have been associated with repetitive movements lacking specific purpose, also known as stereotyped behavior. Dopamine agonists (D2) and noncompetitive N-methyl-D-aspartate receptor antagonists (e.g. ketamine) have been administered in rodent models to induce stereotyped behavior that resembles some motor symptoms of schizophrenia. Recently, a relationship has been found between 5-HT6 receptors (5-HT6Rs) and dopaminergic activity. The present study evaluates the effect of ketamine (5 and 10 mg/kg), alone and in combination with the 5-HT6R agonist E-6837, on the climbing behavior of male mice. Ketamine was administered with an acute (1 day) and subchronic (5 day) scheme. Later, these doses and schemes were combined with an acute scheme of E-6837 (5 and 10 mg/kg). With both the acute and the subchronic schemes, ketamine increased climbing behavior at a dose of 10 mg/kg, and this effect was reversed by E-6837 (at 5 and 10 mg/kg). The present results suggest that there is an interaction between N-methyl-D-aspartate and 5-HT6 receptors in the regulation of climbing behavior. Further research is necessary to provide more evidence on this interaction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Briones-Aranda

Suárez-Santiago

Picazo

et al. 2016

Behavioural Pharmacology

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“…AMPAR containing GluA1 and/or GluA2 subunit upregulation was also observed in mPFC 75 and hippocampal 13 synaptoneurosome fractions at 24 hours post-injection, indicating a rapid-triggered and sustained recruitment of AMPAR in the synapse, consistent with synaptic strengthening. In fact, low doses of ketamine were shown to induce an enhancement of AMPAR-mediated synaptic transmission in the mPFC 145 and hippocampus 146 of rats, as measured by AMPAR currents in pyramidal neurons and extracellular in vivo electrophysiological recordings in CA3 pyramidal neurons respectively. Additionally, application of ketamine to hippocampal slices (non-stimulated 10, 63 and stimulated 147 ) enhanced AMPAR-mediated synaptic potentiation in the CA1 region.…”

Section: Downstream Mechanisms Involved In Ketamine’s Antidepressant mentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

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“…An increase in AMPAR expression in specific synapses is likely to be indicative of a potentiation of AMPAR-mediated synaptic transmission following administration of rapid-acting antidepressants. [211] Indeed, electrophysiological experiments indicate that ketamine application enhances AMPAR-mediated synaptic transmission in pyramidal neurons of mPFC [260] and CA3 region of hippocampus [261] of stress-naive rats.…”

Section: Downstream Pathways Involved In Rapid Antidepressant Actionsmentioning

confidence: 99%

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration to depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine - pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

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Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: An in vivo electrophysiological study on monoaminergic and glutamatergic neurons

Cited by 58 publications

References 53 publications

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Mechanisms of ketamine action as an antidepressant

Convergent Mechanisms Underlying Rapid Antidepressant Action

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