Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects

Pham, Thu Ha; Lavialle-Defaix, Céline; Xu, Xingshun; Deng, Shi‐Xian; Landry, Donald W.; Brachman, Rebecca A.; Denny, Christine A.; Gardier, Alain M.

doi:10.1016/s0924-977x(17)31758-3

Cited by 17 publications

(50 citation statements)

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“…However, it has been recently demonstrated that ketamine's HNK metabolites are biologically active (Moaddel et al, 2013;Singh et al, 2013Singh et al, , 2015Singh et al, , 2016cPaul et al, 2014;Zanos et al, 2016;Cavalleri et al, 2017;Yao et al, 2017;Wray et al, 2018). The (2S,6S)-and (2R,6R)-HNK metabolites have been shown to exert antidepressant-relevant behavioral responses in rodents (Zanos et al, 2016;Pham et al, 2017a, but see Shirayama and Hashimoto, 2018, as well as Yang et al, 2017). Consistent with the more potent antidepressant actions of (R)-ketamine compared with the (S)-ketamine enantiomer, (2R,6R)-HNK was shown to be a more potent antidepressant than (2S,6S)-HNK in several animal tests (Zanos et al, 2016).…”

Section: Pharmacodynamics Of Ketamine and Its Metabolitesmentioning

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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Section: Pharmacodynamics Of Ketamine and Its Metabolitesmentioning

confidence: 99%

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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“…Ketamine has emerged as an alternative treatment for depression due to its fast onset of action and effectiveness in treating patients who are refractory to typical pharmacotherapies; however, the beneficial antidepressant effects of ketamine are accompanied by detrimental adverse effects, including dissociation and abuse potential, limiting its clinical utility (12). We and others reported that, in a number of preclinical models, the ketamine metabolite (2R,6R)-HNK induces antidepressant-relevant effects at similar doses as ketamine, without ketamine's adverse effects at these doses (14,(20)(21)(22)(23)(24)(25)(26)(27)(28). It has been debated, however, whether NMDAR inhibition, the mechanism proposed to underlie the antidepressant effects of ketamine, contributes to the antidepressant effects of (2R,6R)-HNK (14,31,32,40).…”

Section: Discussionmentioning

confidence: 99%

“…(2S,6S)-HNK was also identified as a potential antidepressant, but with lower potency than (2R,6R)-HNK (14). Although the antidepressant-relevant effects of (2R,6R)-HNK were later confirmed by independent research groups using different model systems (20)(21)(22)(23)(24)(25)(26)(27)(28), the mechanism underlying these effects is unknown.…”

Section: Significancementioning

confidence: 99%

Antidepressant-relevant concentrations of the ketamine metabolite (2 R ,6 R )-hydroxynorketamine do not block NMDA receptor function

Lumsden

Troppoli

Myers

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

122

129

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Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine’s antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed in Xenopus oocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 µM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.

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“…Besides different modes of action at the NMDAR receptor, effects of ketamine and d‐cycloserine could differ due to ketamine affecting a broad variety other receptors and neurotransmitter systems including the dopaminergic, noradrenergic, and serotonergic systems (Hara et al., ; Kapur & Seeman, ; Pham et al., ; Yamamoto et al., ). Specifically, in mPFC, ketamine has been found to increase the extracellular levels of 5‐HT within the first 2 hr after ketamine administration (Pham et al., ). Understanding the basis of the inactivity‐dependent suppressions in the lower frequencies is not straight forward.…”

Section: Discussionmentioning

confidence: 99%

Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

Hansen

Agerskov

Arvastson

et al. 2019

Eur J of Neuroscience

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Quantitative electroencephalography from freely moving rats is commonly used as a translational tool for predicting drug‐effects in humans. We hypothesized that drug‐effects may be expressed differently depending on whether the rat is in active locomotion or sitting still during recording sessions, and proposed automatic state‐detection as a viable tool for estimating drug‐effects free of hypo‐/hyperlocomotion‐induced effects. We aimed at developing a fully automatic and validated method for detecting two behavioural states: active and inactive, in one‐second intervals and to use the method for evaluating ketamine, DOI, d‐cycloserine, d‐amphetamine, and diazepam effects specifically within each state. The developed state‐detector attained high precision with more than 90% of the detected time correctly classified, and multiple differences between the two detected states were discovered. Ketamine‐induced delta activity was found specifically related to locomotion. Ketamine and DOI suppressed theta and beta oscillations exclusively during inactivity. Characteristic gamma and high‐frequency oscillations (HFO) enhancements of the NMDAR and 5HT 2A modulators, speculated associated with locomotion, were profound and often largest during the inactive state. State‐specific analyses, theoretically eliminating biases from altered occurrence of locomotion, revealed only few effects of d‐amphetamine and diazepam. Overall, drug‐effects were most abundant in the inactive state. In conclusion, this new validated and automatic locomotion state‐detection method enables fast and reliable state‐specific analysis facilitating discovery of state‐dependent drug‐effects and control for altered occurrence of locomotion. This may ultimately lead to better cross‐species translation of electrophysiological effects of pharmacological modulations.

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Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects

Cited by 17 publications

References 0 publications

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Antidepressant-relevant concentrations of the ketamine metabolite (2 R ,6 R )-hydroxynorketamine do not block NMDA receptor function

Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

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