(S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression

Yokoyama, Rei; Higuchi, Momoko; Tanabe, Wataru; Tsukada, Shinji; Naito, Masashi; Yamaguchi, Takuma; Chen, Lu; Kasai, Atsushi; Seiriki, Kaoru; Nakazawa, Takahiro; Nakagawa, Shinsaku; Hashimoto, Kenji; Hashimoto, Hitoshi; Ago, Yukio

doi:10.1016/j.pbb.2020.172876

Cited by 43 publications

(34 citation statements)

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“…The widespread use of ketamine as a treatment for depression, however, is limited by its dissociative side effects and abuse potential (Krystal et al, 1994;Sassano-Higgins et al, 2016;Zanos et al, 2018). The ketamine metabolite (2R,6R;2S,6S)-hydroxynorketamine (HNK), and predominantly the (2R,6R)-HNK stereoisomer, has been demonstrated to share the antidepressant-relevant effects of ketamine by many (Aguilar-Valles et al, 2020;Casarotto et al, 2021;Chen et al, 2020;Chou et al, 2018;Elmer et al, 2020;Fukumoto et al, 2019;Highland et al, 2018Highland et al, , 2021Lumsden et al, 2019;Pham et al, 2018;Rahman et al, 2020;Riggs et al, 2020;Wray et al, 2019;Zanos et al, 2016Zanos et al, , 2019aZanos et al, , 2019b but not all studies (Yang et al, 2017;Yokoyama et al, 2020). (2R,6R)-HNK lacks the adverse effect burden of ketamine in preclinical studies (Highland et al, 2018;Zanos et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

et al. 2021

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Background: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of ( 2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of ( 2R,6R)-HNK following the direct administration of ( 2R,6R)-HNK. Aim: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of ( 2R,6R)-HNK. Methods: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and ( 2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. Results: In humans, plasma levels of ketamine and norketamine were higher in males than females, while ( 2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of ( 2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct ( 2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of ( 2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Conclusion: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

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Section: Introductionmentioning

confidence: 99%

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

et al. 2021

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“…However, ketamine plays diverse roles in the glutamatergic pathway and other neurotransmitter systems, neurogenesis, inflammation, and even body–brain crosstalk. Furthermore, several studies have suggested the distinct roles of ketamine enantiomers ([ S ]-ketamine and [ R ]-ketamine) and their metabolites ([ 2R,6R ]-HNK and [ 2S,6S ]-HNK) in plasticity and behavior ( Zanos et al, 2016 ; Yamaguchi et al, 2018 ; Hashimoto, 2019 ; Lumsden et al, 2019 ; Yokoyama et al, 2020 ; Highland et al, 2021 ; Wei et al, 2021 ). Thus, mechanisms underlying ketamine’s actions remain controversial.…”

Section: Discussionmentioning

confidence: 99%

A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

Kawatake-Kuno

Murai

Uchida

2021

Front. Behav. Neurosci.

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Major depressive disorder (MDD) is a debilitating disease characterized by depressed mood, loss of interest or pleasure, suicidal ideation, and reduced motivation or hopelessness. Despite considerable research, mechanisms underlying MDD remain poorly understood, and current advances in treatment are far from satisfactory. The antidepressant effect of ketamine is among the most important discoveries in psychiatric research over the last half-century. Neurobiological insights into the ketamine’s effects have shed light on the mechanisms underlying antidepressant efficacy. However, mechanisms underlying the rapid and sustained antidepressant effects of ketamine remain controversial. Elucidating such mechanisms is key to identifying new therapeutic targets and developing therapeutic strategies. Accumulating evidence demonstrates the contribution of the glutamatergic pathway, the major excitatory neurotransmitter system in the central nervous system, in MDD pathophysiology and antidepressant effects. The hypothesis of a connection among the calcium signaling cascade stimulated by the glutamatergic system, neural plasticity, and epigenetic regulation of gene transcription is further supported by its associations with ketamine’s antidepressant effects. This review briefly summarizes the potential mechanisms of ketamine’s effects with a specific focus on glutamatergic signaling from a multiscale perspective, including behavioral, cellular, molecular, and epigenetic aspects, to provide a valuable overview of ketamine’s antidepressant effects.

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“…To date, HNKs have primarily received attention for their therapeutic potential as novel antidepressant compounds. This is largely due to a growing number of preclinical studies demonstrating that (2R,6R)-and/or (2S,6S)-HNK induce behavioral effects in preclinical tests that predict antidepressant effectiveness (see Table 7 for a list of tests and outcomes; results are summarized in Table 8) (Nelson and Trainor, 2007;Zanos et al, 2016Zanos et al, , 2019bChou et al, 2018;Highland et al, 2019;Pham et al, 2018;Fukumoto et al, 2019;Lumsden et al, 2019;Aguilar-Valles et al, 2020;Chen et al, 2020;Elmer et al, 2020;Rahman et al, 2020;Yokoyama et al, 2020).…”

Section: Behavioral Effectsmentioning

confidence: 99%

“…Direct antidepressant-relevant effects of hydroxynorketamines. Independent of the role of HNKs in mediating ketamine's antidepressant effectiveness, a growing number of studies have demonstrated that direct administration of (2R,6R)-HNK and, to a lesser extent, (2S,6S)-HNK induces both rapid (observed within hours) and long-lasting (persisting days to weeks after treatment) behavioral effects in preclinical rodent studies used to predict antidepressant effectiveness (Nelson and Trainor, 2007;Zanos et al, 2016Zanos et al, , 2019bChou et al, 2018;Highland et al, 2019;Pham et al, 2018;Fukumoto et al, 2019;Lumsden et al, 2019;Chen et al, 2020;Elmer et al, 2020;Ko et al, 2020;Rahman et al, 2020;Yokoyama et al, 2020); namely, a single systemic (intraperitoneal) injection of (2R,6R)-HNK reduces immobility time in the mouse forced swim test, an effect which has been observed at the following post-treatment times: 1 hour (5-125 mg/kg, i.p.) (Zanos et al, 2016(Zanos et al, , 2019bHighland et al, 2019;Lumsden et al, 2019;Aguilar-Valles et al, 2020;Rahman et al, 2020), 24 hours (5-125 mg/kg, i.p.)…”

Section: Behavioral Effectsmentioning

confidence: 99%

“…In addition to exerting rapid antidepressant-relevant effects (Nelson and Trainor, 2007;Zanos et al, 2016Zanos et al, , 2019bChou et al, 2018;Highland et al, 2019;Pham et al, 2018;Fukumoto et al, 2019;Lumsden et al, 2019;Ko et al, 2020;Rahman et al, 2020;Yokoyama et al, 2020), (2R,6R)-and (2S,6S)-HNK may also have prophylactic stress-protective actions (Chen et al, 2020) and analgesic properties (Kroin et al, 2019), as well as effects on aggression and social behaviors (Ye et al, 2019;Chou, 2020). Although the full mechanisms underlying the preclinically observed behavioral effects of HNKs are still being elucidated, a number of potential sites of action have been identified.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

et al. 2021

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The following authors declare competing financial interests: R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro-and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.M., C.T., C.A.Z., and T.G. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.A.Z., and C.T. have assigned their patent rights to the United States government but will share a percentage of any royalties that may be received by the government. P.Z. and T.G. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7, LLC, during the preceding 3 years. All other authors declare no competing interests.

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(S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression

Cited by 43 publications

References 34 publications

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

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