Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats

Burgdorf, Jeffrey; Kroes, Roger A.; Zhang, Xiao lei; Gross, Amanda L.; Schmidt, Matthew; Weiss, Craig; Disterhoft, John F.; Burch, Ronald M.; Stanton, Patric K.; Moskal, Joseph R.

doi:10.1016/j.bbr.2015.07.039

Cited by 51 publications

(36 citation statements)

References 40 publications

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“…Bath-applied GLYX-13 as well as another glycine partial agonist, D-cycloserine enhances long term potentiation (LTP) in hippocampal Schaffer collateral-CA1 synapses (Zhang et al, 2008), and in vivo administration of GLYX-13 enhances subsequent hippocampal slice LTP (Burgdorf et al, 2015b), suggesting that glycine site partial agonist properties underlie the actions of GLYX-13 on synaptic plasticity in the hippocampus. GLYX-13 administration also produces a long-lasting increase in NMDA current conductance (Burgdorf et al, 2015b), and the observations that GluN2B selective antagonists block the effects of GLYX-13 on NMDA currents and LTP indicate a role of this receptor subtype in the actions of GLYX-13. These effects of GLYX-13 on plasticity-related processes could be related to the cognitive enhancing and antidepressant actions of GLYX-13, as well as the ability of GLYX-13 to block the effects of ketamine in a declarative memory task (Rajagopal et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…GLYX-13 is an NMDA modulator with glycine site partial agonist properties and ketamine is an activity dependent nonselective NMDA open channel blocker Traynelis et al, 2010). Bath-applied GLYX-13 as well as another glycine partial agonist, D-cycloserine enhances long term potentiation (LTP) in hippocampal Schaffer collateral-CA1 synapses (Zhang et al, 2008), and in vivo administration of GLYX-13 enhances subsequent hippocampal slice LTP (Burgdorf et al, 2015b), suggesting that glycine site partial agonist properties underlie the actions of GLYX-13 on synaptic plasticity in the hippocampus. GLYX-13 administration also produces a long-lasting increase in NMDA current conductance (Burgdorf et al, 2015b), and the observations that GluN2B selective antagonists block the effects of GLYX-13 on NMDA currents and LTP indicate a role of this receptor subtype in the actions of GLYX-13.…”

Section: Discussionmentioning

confidence: 99%

“…However, the antidepressant actions of both GLYX-13 and ketamine are blocked by pretreatment with an AMPA receptor antagonist, indicating a requirement for glutamate-AMPA receptor activity (Burgdorf et al, 2013;Li et al, 2010;Maeng et al, 2008) 4 We have previously demonstrated that ketamine increases synaptic number and function in the mPFC, and shown that these effects depend on mTORC1 signaling (Li et al, 2010;Li et al, 2011). GLYX-13 is reported to enhance neuroplasticity suggesting that it may also enhance synaptic function (Burgdorf et al, 2015a(Burgdorf et al, , 2015b). In the current study, we compared the influence of GLYX-13 and ketamine on the mTORC1-signaling pathway and on the number and function of spine synapses in the rat mPFC.…”

Section: Introductionmentioning

confidence: 94%

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GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

Liu

Duman

Kato

et al. 2016

Neuropsychopharmacol

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GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

Liu

Duman

Kato

et al. 2016

Neuropsychopharmacol

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“…Importantly, GLYX-13 reverses chronic stress-induced reduction in NMDAR-dependent LTP [217], which is a mechanism hypothesized to mediate its antidepressant actions. Moreover, similar to ketamine, GLYX-13 enhances hippocampal LTP in brain slices taken 24 h and 7 days following a single in vivo injection in rodents [218].…”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

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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“…Another engaging aspect regarding the mechanism of action of rapastinel refers to the fact that its enduring antidepressant effects are associated with a metaplasticity process in the medial PFC (mPFC) and hippocampus 69. Metaplasticity is induced by synaptic and cellular activity and manifested as a change in the ability to induce subsequent synaptic plasticity, such as LTP, representing therefore in fact a higher-order form of synaptic plasticity 70.…”

Section: Molecular Determinants Of the Antidepressant Effect Of Rapasmentioning

confidence: 99%

Modulation of the activity of <em>N</em>-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13)

Vasilescu¹,

Schweinfurth²,

Borgwardt³

et al. 2017

NDT

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Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13), a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive–compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation.

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Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats

Cited by 51 publications

References 40 publications

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

Convergent Mechanisms Underlying Rapid Antidepressant Action

Modulation of the activity of <em>N</em>-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13)

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