(R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation

Oliveira, Elifrances Galdino de; Lima, Daniela Delwing-de; Júnior, José Carlos da Silva; Barbosa, Maria Luisa; Silva, Severina Cássia de Andrade; Santana, Jonata Henrique de; Santos, Osvaldo; Lira, Eduardo Carvalho; Lagranha, Cláudia Jacques; Duarte, Filipe S.; Gomes, Dayane Aparecida

doi:10.1007/s00406-023-01629-3

Cited by 3 publications

(3 citation statements)

References 61 publications

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“…In line with our findings, a recent study reported that R-ket attenuated anxiety-related behaviors in an animal model of maternal immune activation which is commonly used to study neurodevelopmental disorders including schizophrenia (de Oliveira et al, 2023). This anxiolytic effect was linked to its antioxidant and anti-inflammatory effects in the prefrontal cortex of the mice (de Oliveira et al, 2023). Thus, the anxiolytic effects of R-norket observed in our study might be due to this anti-inflammatory action rather than via GluN2D-mediated signaling.…”

Section: Discussionsupporting

confidence: 92%

“…We also show that R‐norket improves anxiety‐like behaviors in KO females—suggesting GluN2D is not involved in mediating the effects of R‐norket on this behavior in female mice. In line with our findings, a recent study reported that R‐ket attenuated anxiety‐related behaviors in an animal model of maternal immune activation which is commonly used to study neurodevelopmental disorders including schizophrenia (de Oliveira et al, 2023). This anxiolytic effect was linked to its antioxidant and anti‐inflammatory effects in the prefrontal cortex of the mice (de Oliveira et al, 2023).…”

Section: Discussionsupporting

confidence: 92%

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Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Vinnakota,

Schroeder,

et al. 2023

J of Neuroscience Research

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Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis‐like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia‐relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia‐relevant NMDAR antagonist‐induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia‐relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S‐ketamine enantiomer (S‐ket), and the ketamine metabolite R‐norketamine (R‐norket) on locomotor activity, anxiety‐related behavior, and recognition and short‐term spatial memory. GluN2D‐KO mice showed a blunted locomotor response to R‐norket, S‐ket, and PCP, a phenotype present in both sexes. GluN2D‐KO mice of both sexes showed an anxious phenotype and S‐ket, R‐norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S‐ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex‐specific effects of NMDAR antagonists and on the differential effects of the R‐ and S‐ket enantiomers.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Vinnakota,

Schroeder,

et al. 2023

J of Neuroscience Research

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“…Tan and colleagues have reported a protective effect of prophylactic (R)-ketamine in rodent models generating schizophrenia-like behaviors in offspring after maternal immune activation [67]. Concordant findings were subsequently reported [68].…”

Section: Other Potential Therapeutic Applicationsmentioning

confidence: 89%

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders

Shafique,

Demers,

Biesiada

et al. 2024

IJMS

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NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.

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New treatment strategies for mental health

Hashimoto,

Schmitt

2023

Eur Arch Psychiatry Clin Neurosci

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(R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation

Cited by 3 publications

References 61 publications

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders

New treatment strategies for mental health

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