Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening

Talbot, Jeffery N.; Geffert, Laura M.; Jorvig, Jessica E.; Goldstein, Ruben I.; Nielsen, Cienna L.; Wolters, Nicholas E.; Amos, Mary Ellen; Munro, Caitlin; Dallman, Elizabeth; Mereu, Maddalena; Katz, Jonathan L.; Indarte, Martin; Madura, Jeffry D.; Choi, Hailey J.; Leak, Rehana K.; Surratt, Christopher K.

doi:10.1016/j.pbb.2016.08.007

Cited by 12 publications

(10 citation statements)

References 61 publications

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“…To clarify whether ketamine's action to prevent mGlu 2/3 receptor agonist-induced hyperthermia is due to NMDAR inhibition, we assessed three distinct NMDAR antagonists: (i) (+)-MK-801, a noncompetitive NMDAR antagonist, which acts at the same phencyclidine (PCP)/ketamine site of the NMDAR; (ii) (±)-CPP, a competitive NMDAR antagonist; and (iii) Ro 25-6981, a GluN2B-specific NMDAR antagonist; we used doses known to exert putative antidepressant-relevant actions in rodents (15,33,(72)(73)(74)(75)(76) and to induce NMDAR inhibition-mediated behaviors (75,(77)(78)(79). Administration of these NMDAR antagonists did not prevent mGlu 2/3 receptor agonist-induced hyperthermia ( Fig.…”

Section: Resultsmentioning

confidence: 99%

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

Zanos

Highland

Stewart

et al. 2019

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

114

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Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu 2 ) and 3 (mGlu 3 ) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu 2/3 receptor agonist (LY379268)induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30-to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu 2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3 −/− , gene. Combined subeffective doses of the mGlu 2/3 receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu 2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu 2 receptor function in clinical trials for treatment-resistant depression either alone or in combination. ketamine | hydroxynorketamine | antidepressant | mGlu 2 receptor |

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Section: Resultsmentioning

confidence: 99%

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

Zanos

Highland

Stewart

et al. 2019

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

114

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“…While ketamine also increased sucrose intake in ZnD rats, the effect was not statistically significant. It is known that a single dose of either ketamine or other NMDAR antagonists like Ro induces antidepressant-like potency in preclinical stress-related paradigms [32,44,45]. On the other hand, classic antidepressant drugs like fluoxetine or desipramine are effective only after chronic treatment [19,21].…”

Section: Discussionmentioning

confidence: 99%

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction

Pochwat

Domin

Rafało-Ulińska

et al. 2020

IJMS

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Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study.

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“…Fluoxetine (20 mg kg −1 day −1 ) or saline was administrated (i.p.) prior to and concurrent with CSDS for 21 days (Han, Lee, & Leem, ; Lehmann, Geddes, Lee, & Herkenham, ; Talbot et al, ). Twenty‐four hours after CSDS, C57 mice were examined with behavioral tests.…”

Section: Methodsmentioning

confidence: 99%

Effect of Toll‐like receptor 4 on depressive‐like behaviors induced by chronic social defeat stress

et al. 2020

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Introduction A growing body of evidence suggests that stress is an important factor in depression, and pro‐inflammatory cytokines contribute to the occurrence and development of depression in both animal models and human patients. Toll‐like receptor 4 (TLR4) has been shown to be a key innate immune pattern recognition receptor involved in the regulation of stress responses and inflammation. However, the exact effects of TLR4 on depressive‐like behaviors induced by chronic social defeat stress (CSDS) are not known. Methods In this study, the effects of TLR4 on depressive‐like behaviors were investigated in an animal model of depression induced by CSDS. The depressive‐like behaviors were assessed by forced swimming test (FST), social interaction test (SIT), and light–dark box test (LDT). The protein expressions of TLR4 and tumor necrosis factor‐α (TNF‐α) in the hippocampus were measured using Western blotting. Results We found that CSDS increased TLR4 protein levels in the hippocampus and induced behavioral despair in FST, social avoidance in SIT, and anxiety‐like behavior in LDT. Fluoxetine normalized the increased expression of TLR4 and reversed behavioral despair, social avoidance, as well as anxiety‐like behavior induced by CSDS. However, directly blocking TLR4, by using either TLR4 inhibitor TAK‐242 or knockout of TLR4, only inhibited behavioral despair, but not social avoidance or anxiety‐like behavior induced by CSDS. Conclusions These results demonstrate a specific modulating role of TLR4 in behavioral despair induced by CSDS and suggest that TAK‐242 may be a beneficial treatment for patients with behavioral despair.

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Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening

Cited by 12 publications

References 61 publications

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction

Effect of Toll‐like receptor 4 on depressive‐like behaviors induced by chronic social defeat stress

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Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening

Cited by 12 publications

References 61 publications

( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions

( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction

Effect of Toll‐like receptor 4 on depressive‐like behaviors induced by chronic social defeat stress

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( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions

( 2R,6R )-hydroxynorketamine exerts mGlu ₂ receptor-dependent antidepressant actions