Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression

Jardin, Kristian Gaarn du; Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina; Sanchéz, Connie; Wegener, Gregers

doi:10.1007/s00213-016-4327-5

Cited by 70 publications

(46 citation statements)

References 71 publications

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“…clear antidepressant-like response in FSL rats at 1 as well as 48 hr after dosing (Liebenberg et al, 2015;du Jardin et al, 2016). Similar findings have been published for other doses of ketamine in several preclinical models (Garcia, Comim, Valvassori, R eus, Barbosa et al, 2008;Gigliucci et al, 2013;Zhou, Wang, Yang, Li, Zhou, & Yang, 2013).…”

Section: Discussionsupporting

confidence: 85%

“…The dose (15 mg/kg) and formulation (S‐ketamine HCl) of ketamine used in the present manuscript has been demonstrated to elicit a clear antidepressant‐like response in FSL rats at 1 as well as 48 hr after dosing (Liebenberg et al, ; du Jardin et al, ). Similar findings have been published for other doses of ketamine in several preclinical models (Garcia, Comim, Valvassori, Réus, Barbosa et al, ; Gigliucci et al, ; Zhou, Wang, Yang, Li, Zhou, & Yang, ).…”

Section: Discussionmentioning

confidence: 94%

“…In addition to modulation of glutamatergic neurotransmission, ketamine has been found to modify multiple aspects of serotonergic neurotransmission, including increased efflux in the prefrontal cortex (Amargós‐Bosch, López‐Gil, Artigas, & Adell, ; Yamamoto, Ohba, Nishiyama, Harada, Kakiuchi, Tsukada, & Domino, ; Nishitani, Nagayasu, Asaoka, Yamashiro, Shirakawa, Nakagawa, & Kaneko, ). Our group as well as others have shown that the antidepressant‐like activities of ketamine in rats depend on endogenous 5‐hydroxytryptamine (5‐HT; serotonin) in the forced swim test (Gigliucci, O'dowd, Casey, Egan, Gibney, & Harkin, ; Du Jardin, Liebenberg, Müller, Elfving, Sanchez, & Wegener, ). Thus, in addition to glutamate, serotonergic neurotransmission may be implicated in the antidepressant‐like effects of ketamine.…”

Section: Introductionmentioning

confidence: 90%

“…We have previously reported that FSL rats respond to a single administration of ketamine (Liebenberg, Joca, & Wegener, 2015;du Jardin et al, 2016). Thus, to gain novel insights into the antidepressant mechanisms of ketamine and obtain a more comprehensive understanding of the serotonergic and glutamatergic neurotransmitter systems in FSL and FRL rats, we investigated the expression of serotonergic and glutamatergic genes in the brains of FSL and FRL rats in response to a single dose of ketamine.…”

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confidence: 99%

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Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine

Jardin

Müller

Sanchéz

et al. 2016

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Major depressive disorder (MDD) is associated with dysfunctional serotonergic and glutamatergic neurotransmission, and the genetic animal model of depression Flinders Sensitive Line (FSL) rats display alterations in these systems relatively to their control strain Flinders Resistant Line (FRL). However, changes on transcript level related to serotonergic and glutamatergic signaling have only been sparsely studied in this model. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has fast-onset antidepressant properties, and recent data implicate serotonergic neurotransmission in ketamine's antidepressant-like activities in rodents. Here, we investigated the transcript levels of 40 genes involved in serotonergic and glutamatergic neurotransmission in FSL and FRL rats in response to a single dose of ketamine (15 mg/kg; 90 min prior to euthanization). Using real-time quantitative polymerase chain reaction, we studied the effect of ketamine in the hippocampus, whereas strain differences were investigated in both hippocampus and frontal cortex. The expression of genes involved in serotonergic and glutamatergic neurotransmission were unaffected by a single dose of ketamine in the hippocampus. Relative to FRL rats, FSL rats displayed enhanced hippocampal transcript levels of 5-ht , and P11, whereas the expression was reduced for 5-ht , Nr2a, and Mglur2. In the frontal cortex, we found higher transcript levels of 5-ht and Mglur2, whereas the expression of 5-ht was reduced in FSL rats. Thus, ketamine is not associated with hippocampal alterations in serotonergic or glutamatergic genes at 90 min after an antidepressant dose. Furthermore, FSL rats display serotonergic and glutamatergic abnormalities on gene expression level that partly may resemble findings in MDD patients.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 90%

mentioning

confidence: 99%

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Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine

Jardin

Müller

Sanchéz

et al. 2016

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“…Several studies suggest that increased 5-HT levels are necessary for the antidepressant-like effects of ketamine in rodents. For instance, pharmacological treatments that reduce 5-HT levels in the brain abolished ketamine's antidepressant behavioral effects in the forced-swim test (du Jardin et al, 2016;Pham et al, 2017b) and in the novelty-suppressed feeding test (Fukumoto et al, 2014) in rodents. In addition, higher extracellular 5-HT levels were positively correlated with ketamine's antidepressant activity in the forcedswim test in mice (Pham et al, 2017b).…”

Section: E Monoaminergic Receptors and Transportersmentioning

confidence: 99%

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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Ketamine, a racemic mixture consisting of ()- and ()-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of -methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

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Vortioxetine for depression in adults

Koesters

Ostuzzi

Guaiana

et al. 2017

Cochrane Database of Systematic Reviews

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The place of vortioxetine in the treatment of acute depression is unclear. Our analyses showed vortioxetine may be more effective than placebo in terms of response, remission and depressive symptoms, but the clinical relevance of these effects is uncertain. Furthermore, the quality of evidence to support these findings was generally low. In comparison to SNRIs, we found no advantage for vortioxetine. Vortioxetine was less effective than duloxetine, but fewer people reported adverse effects when treated with vortioxetine compared to duloxetine. However, these findings are uncertain and not well supported by evidence. A major limitation of the current evidence is the lack of comparisons with the SSRIs, which are usually recommended as first-line treatments for acute depression. Studies with direct comparisons to SSRIs are needed to address this gap and may be supplemented by network meta-analyses to define the role of vortioxetine in the treatment of depression.

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Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression

Cited by 70 publications

References 71 publications

Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine

Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Vortioxetine for depression in adults

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