An integrative view on the cell-type-specific mechanisms of ketamine's antidepressant actions

Trends in Neurosciences, Год журнала: 2024, Номер 47(3), С. 195 - 208

Опубликована: Янв. 21, 2024

Язык: Английский

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The role of mGluR5 on the therapeutic effects of ketamine in Wistar rats

Psychopharmacology, Год журнала: 2024, Номер 241(7), С. 1399 - 1415

Опубликована: Март 9, 2024

Abstract Rationale Ketamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has complex mechanism of action that involve alterations other glutamate receptors. The metabotropic receptor 5 (mGluR5) been investigated relation to the psychotic properties ketamine, while its role mediating therapeutic ketamine remains unknown. Objectives We mGluR5 on anxiolytic fear memory-related adult male Wistar rats. Methods Two sets experiments were conducted. first utilized positive allosteric modulator CDPPB investigate how acute activation regulates (10 mg/kg). then tested synergistic antidepressant effect antagonism by combining MTEP with sub-effective (1 Behavioral despair, locomotor activity, anxiety-like behavior, memory respectively assessed forced swim test (FST), open field (OFT), elevated plus maze (EPM), auditory conditioning. Results Enhancing activity via occluded without changing activity. Furthermore, concomitant administration exhibited robust effect. + treatment, however, blocked observed sole or low ketamine. Conclusions These findings suggest suppressed is required for Consequently, enhances effectiveness but eliminates effects.

Язык: Английский

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Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care

Anesthesiology, Год журнала: 2024, Номер 141(2), С. 222 - 237

Опубликована: Июнь 10, 2024

During the last 100 years, role of anesthesiologists in psychiatry has focused primarily on facilitating electroconvulsive therapy and mitigating postoperative delirium other perioperative neurocognitive disorders. The discovery rapid sustained antidepressant properties ketamine, early results suggesting that general anesthetic drugs (including nitrous oxide, propofol, isoflurane) have properties, positioned at a new frontier treatment neuropsychiatric Moreover, shared interest understanding biologic underpinnings as psychotropic agents is eroding traditional academic boundaries between anesthesiology psychiatry. This article presents brief overview novel antidepressants identifies promising future candidates for depression. authors issue call to action outline strategies foster collaborations psychiatrists they work toward common goals repurposing addressing mood disorders surgical patients.

Язык: Английский

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S-ketamine exposure in early postnatal period induces social deficit mediated by excessive microglial synaptic pruning

Molecular Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

The impact of general anesthetics on neurodevelopment is highly controversial in terms clinical and preclinical studies. Evidence mounted recent years indicated development social cognitions was more susceptible to anesthesia early life. However, the behavioral characterization during adolescence underlying mechanisms remains unclear. Herein, we observed that postnatal S-ketamine exposure specifically induced deficits sociability cognition via a machine learning assistant analysis toolbox- Social Behavioral Atlas (SBeA). Furthermore, constantly activates microglia prefrontal cortex (PFC), mediating excessive synaptic pruning dendritic structural abnormalities, leading overexcitation excitatory transmission. Notably, activated Stat1-Arg1 pathway microglia. Downregulating Arg1 expression or prophylactic administrating selective inhibitor nor-NOHA could reverse microglial overactivation attenuate neurodevelopmental disturbance by exposure. Our study identifies abnormal phenotypes reveals potential target for preventing anesthesia-related abnormalities.

Язык: Английский

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Ketamine induced synaptic plasticity operates independently of long-term potentiation

Neuropsychopharmacology, Год журнала: 2024, Номер 49(11), С. 1758 - 1766

Опубликована: Июнь 19, 2024

Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian are two such by which neuronal synapses can be altered. Although these processes mechanistically distinct, they converge on downstream regulation of AMPA receptor activity modify glutamatergic neurotransmission. However, much remains explored regarding how prominent forms interact. Ketamine, a rapidly acting antidepressant, increases transmission pharmacologically-induced homeostatic plasticity. Here, we demonstrate that still intact in have undergone scaling ketamine after either systemic injection or perfusion onto hippocampal brain slices. We also investigated this relationship the context stress induced chronic exposure corticosterone (CORT) better model circumstances under may used as an antidepressant. found CORT anhedonia-like behavioral phenotype mice but did not impair long-term potentiation (LTP) induction. Furthermore, does impact intersection mechanisms, from CORT-exposed demonstrated ketamine-induced LTP succession. These results provide mechanistic explanation for treatment depression integrity learning memory encoded LTP.

Язык: Английский

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Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 2, 2023

Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one auxiliary subunits, which controls assemblies, surface trafficking gating AMPARs. Here, we show that ketamine rescues both depressive-like behaviors decreased AMPARs-mediated neurotransmission by recruitment TARP-γ8 postsynaptic sites in ventral hippocampus stressed male mice. Furthermore, are abolished selective blockade TARP-γ8-containing or uncoupling from PSD-95. Overexpression reverses chronic stress-induced attenuation neurotransmission. Conversely, knockdown excitatory neurons prevents ketamine.

Язык: Английский

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Targeting N‐methyl‐D‐aspartate Receptors in Neurodegenerative Diseases

Опубликована: Фев. 12, 2024

N-methyl-D-aspartate receptors (NMDARs) are the main class of ionotropic receptor for ex-citatory neurotransmitter glutamate. It plays a crucial role in permeability Ca2+ ions and excitatory neurotransmission brain. Being heteromeric receptors, they composed sev-eral subunits, including two obligatory GluN1 subunits (eight splice variants) regulatory GluN2 (GluN2A~D) and/or GluN3 (GluN3A~B) subunits. Widely distributed brain, regulate other systems therefore involved essential functions such as synaptic transmission, learning memory, plasticity, excitotoxicity. The present review will discuss physiopathological impacts NMDAR particularly GluN2A GluN2B subu-nits cognitive processes neurodegenerative diseases (Alzheimer's disease, Huntington's Parkinson's disease). pharmacology different antagonists their po-tentialities be presented. In particular, focus given on fluoroethylnormemantine (FENM), an investigational drug with very promising developments tomography radiotracer NMDARs, anxiolytic post-traumatic stress disorder neuroprotective agent Alzheimer's disease.

Язык: Английский

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The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Год журнала: 2023, Номер 129, С. 110910 - 110910

Опубликована: Дек. 6, 2023

Conventional antidepressants that target monoaminergic receptors require several weeks to be efficacious. This lag represents a significant problem in the currently available treatments for serious depression. Ketamine, acting as an N-methyl-d-aspartate receptor antagonist, was shown have rapid antidepressant-like effects, marking advancement study of mood disorders. However, side effects and adverse reactions limit its clinical use. Considering limitations ketamine, it is crucial further define network targets ketamine. The action ketamine antidepressant thought mediated by glutamate system. It believed synaptic plasticity essential antidepressant. Other mechanisms include involvement γ-aminobutyric acidergic (GABAergic), 5-HTergic systems, recent studies linked astrocytes ketamine's effects. interactions between these systems exert synergistic effect through neural circuits molecular mechanisms. Here, we discuss underlying work will help explain how are responsible rapidly aid discovery new therapeutic approaches major depressive disorder.

Язык: Английский

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Psychiatric and legal considerations for ketamine treatment within prison settings

Frontiers in Psychiatry, Год журнала: 2024, Номер 15

Опубликована: Апрель 18, 2024

The fundamental right to equivalence of health care in prison settings encompasses the provision medication address mental conditions. Considering increased risk for self-harm among individuals dealing with depression, limited effectiveness conservative antidepressants is a major challenge psychiatry. high prevalence suicidal tendencies within populations underscores imperative state-of-the-art pharmacological treatment uphold adequate standards. Notably, denial access effective could be deemed violation human rights people living according international treaties, domestic law, and United Nations normative standards detention. This article presents authors' perspective on accessibility ketamine settings, discussing psychiatric legal considerations as well current challenges this context. Implementing novel psychopharmacological interventions may alleviate distress experienced by struggling depressive symptoms suicidality. At same time, unprecedented alternatives bring along potential issues, including understanding long-term effects abuse. Given scarce data-availability, pressing need exists further research benefits risks populations.

Язык: Английский

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Neuroplasticity in the transition from acute to chronic pain

Neurotherapeutics, Год журнала: 2024, Номер unknown, С. e00464 - e00464

Опубликована: Окт. 1, 2024

Язык: Английский

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