dizocilpine (MK801) / Merck (MSD) - LARVOL DELTA

The Effect of Exposure to Music on Spatial Learning and Memory in Rats. (PubMed, Noro Psikiyatr Ars) - "For the remaining two groups, one was injected with ketamine and the other was injected with MK-801. The effect of music on NMDARs may be at levels that do not change PPI values. Considering that parameters like the duration and intensity of music may cause stress, repeating the experiment with different conditions may provide new clues."

Journal • Preclinical

Association Between Gene Polymorphisms of RSPO2 of the Wnt Signaling Pathway and Schizophrenia in the Korean Population. (PubMed, Psychiatry Investig) - "The findings indicate that RSPO2 gene polymorphisms, particularly rs374810 and rs423940, may contribute to schizophrenia susceptibility. Therefore, RSPO2 expression may be associated with the susceptibility to schizophrenia in the Korean population."

Journal • CNS Disorders • Psychiatry • Schizophrenia • RSPO2

The nitric oxide synthase inhibitor 7-nitroindazole attenuates social withdrawal and memory impairments induced by Blockade of the NMDA receptor in the rat. (PubMed, Psychopharmacology (Berl)) - "The present results indicate that 7-NI is sensitive to glutamate blockade since it decreased behavioural impairments resembling the negative symptoms and cognitive deficits of schizophrenia. Moreover, these findings corroborate the potential of 7-NI as an adjunctive molecule for the medication of schizophrenia."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • NOS1

Transcriptomic analysis reveals pathway-specific targets for hyperlocomotion and social withdrawal in mouse models of schizophrenia. (PubMed, Neuroscience) - "Differentially expressed genes in the MK-801 model displayed a modest correlation with that of schizophrenia patients (r = 0.40, p = 2.7 × 10-6), higher than the MAM model (r = 0.15, p = 0.23), underscoring NMDAR antagonism's relevance to the core pathology of the disorder. Using weighted gene co-expression network analysis, we identified 28co-expression modules across the mouse models, with 11modules significantly associated with individual schizophrenia-related behavioral endophenotypes.Notably, the brown module (linked to hyperlocomotion, r = 0.55, p = 0.01) and the darkgrey module (associated with social withdrawal, r = -0.71, p = 3 × 10-4)were enriched in Wnt and PI3K/Akt signaling pathways, respectively.Pharmacological inhibition of these two pathways specifically rectified corresponding behavioral anomalies in the MK-801 model, highlighting the critical role of altered Wnt and PI3K/Akt signaling in these behavioral domains of schizophrenia-related..."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Exploring effects of chronic d-cycloserine administration on expression of GluN2 subunits and tripartite synaptic transmission in thalamocortical pathway. (PubMed, Br J Pharmacol) - "Chronic d-cycloserine (25 μM and 2 mg·kg-1) down-regulated GluN2C without affecting GluN2A/GluN2B but increased GluN2-related astroglial l-glutamate/d-serine release. Higher d-cycloserine dose (>60 μM; >5 mg·kg-1) inactivated GluN2C, but increased GluN2A related astroglial release. These results indicate that dose-dependent activation and inactivation of GluN2C by d-cycloserine is possibly involved in its efficacy on negative symptom of schizophrenia, but with a narrow therapeutic window."

Journal • CNS Disorders • Depression • Psychiatry • Schizophrenia • GRIN2A • GRIN2B

Functional Characterization and Expression Patterns of novel_circ_037817 in Schizophrenia Patients. (PubMed, Mol Neurobiol) - "Under MK-801 treatment conditions, knockdown of novel_circ_037817 expression increased cell viability, inhibited apoptosis, increased Bcl-2 expression, and reduced Bax expression. In summary, this study provides the first evidence that novel_circ_037817 may be involved in SCZ and offers a novel target for SCZ intervention."

IO biomarker • Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia • BCL2 • IL1B • TNFA

A zebrafish model of benzodiazepine-refractory status epilepticus for whole organism discovery of novel anti-seizure treatments (AES 2025) - "The pharmacology of PXN-related SE was probed using inhibitors of NMDAR (MK801) and brain-specific alpha7 nicotinic AChRs (MLA); a positive allosteric modulator of GABAR (diazepam, DZP); and the antidote atropine + 2-pralidoxime (A/2PAM). We show that PXN has LD50(6 hours)= 125uM and at earlier timepoints results in immobility, L-bend contracture, and dramatic brain region-specific increases in tonic calcium fluorescence in still living fish, consistent with status epilepticus. Similar to rodent models of PXN-related SE, our study confirms the key roles of NMDAR and central effects of cholinergic excess to PXN-related SE in zebrafish, as well as its poor response to benzodiazepine treatment. To the best of our knowledge, no existing zebrafish models of seizures demonstrate benzodiazepine resistance. These findings will now enable high-throughput screening to identify novel counter-measures that may control refractory SE related to organophosphate exposure and other..."

CNS Disorders • Epilepsy

Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice. (PubMed, Mol Psychiatry) - "Finally, we showed that the anti-inflammatory and antidepressant effects are linked, perhaps as convergent outcomes, by using another NMDA receptor antagonist, MK-801, and the mTOR signaling inhibitor, rapamycin. These findings highlight ketamine's multifaceted mechanisms of action, underscoring its potential as a treatment for MDD, particularly in patients with significant inflammation."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mood Disorders • Psychiatry • CD69 • HAVCR2 • MRC1

Precision neural activity mapping in brain organoids through field potential imaging with ultra-high-density CMOS microelectrode array (Neuroscience 2025) - "In cortical organoids, the GABAA receptor antagonist picrotoxin increased propagation velocity, whereas the NMDA receptor antagonist MK-801 broadly reduced propagation area with regionally localized enhancements...Connectivity analysis further demonstrated that treatment with 4-aminopyridine significantly enhanced inter-organoid coupling. This single-cell-resolved, high-density FPI approach enables robust quantification of neuronal firing, connectivity, propagation dynamics, and frequency characteristics. Our platform offers a powerful tool for investigating functional neural circuits in brain organoids and assembloids, with significant potential for applications in drug screening and disease modeling."

CNS Disorders

QSAR design, syntheses, and in vitro assessment of bridged polycyclic alkyl aryl amines as uncompetitive nmda receptor antagonists for treatment of neurodegenerative disorders (Neuroscience 2025) - "To address this issue, uncompetitive NMDAR antagonism continues to be a worthwhile pursuit, as demonstrated by FDA approval of three compounds in that class - memantine for treatment of Alzheimer's Disease (AD), amantadine for treatment of Parkinson's Disease (PD), and the recent approval of Ketamine for treatment resistant major depressive disorder...Binding affinities at the NMDAR PCP site, measured via [³H]-MK-801 radioligand assays, ranged from 679 nM to 10,000 nM...Preliminary 2D QSAR model studies demonstrated strong predictive performance amongst the training and test set compound series (R² = 0.84, Q² = 0.76), while molecular docking was used to gain further insight into SAR relationships within the PCP binding site. These results establish bridged polycyclic alkyl aryl amine scaffolds as promising uncompetitive NMDAR antagonists and provide new insight into strategies for developing therapeutic agents targeting neurodegenerative disorders."

Late-breaking abstract • Preclinical • Alzheimer's Disease • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

Developing EEG-based Biomarker Systems in Rodents and Primates for Drug Response Evaluation: Deep Learning-Based Prediction Model Construction (Neuroscience 2025) - "Specifically, we evaluated resting-state EEG and AERP signals, including auditory habituation (AH), mismatch negativity (MMN), and auditory steady-state response (ASSR), following the administration of MK-801, an NMDA receptor antagonist...Moreover, we introduced the predictive contribution score (PCS), which facilitated identification of proof-of-mechanism markers, classification explainability, and the generation of inter-species hypotheses. Our findings have the potential to significantly advance CNS drug development by providing insights that improve clinical trial strategies and elucidate the neurophysiological mechanisms of drug action."

Late-breaking abstract • Preclinical • CNS Disorders

Prefrontal dysfunction impairs social affective behaviors in a rat model of schizophrenia (Neuroscience 2025) - "Consistent results were observed following treatment with diazepam, an anxiolytic drug that enhances inhibitory signaling in the central nervous system. This study demonstrates that MK-801-induced model rats of schizophrenia show deficits in social affective behaviors, which can be linked to an excitatory/inhibitory imbalance in the mPFC. We are currently further investigating this relationship from behavioral, neuroscientific, and genetic perspectives."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Sex-dependent effects of psychotomimetic and antipsychotic drugs on risky decision-making (Neuroscience 2025) - "MK-801, an NMDA antagonist commonly used as a pharmacological model of schizophrenia, increased risk-taking behavior selectively in males...We also assessed the effects of the atypical antipsychotic risperidone on risky decision-making...Preliminary data suggests that joint treatment evokes increased risk-aversion without impacting punishment sensitivity. Collectively, these data suggest that risky decision-making is impacted in sex-specific fashion by both psychotomimetic and antipsychotic drugs, which has important implications for managing aberrant decision-making and risk processing in schizophrenia."

CNS Disorders • Psychiatry • Schizophrenia

Targeting clozapine responsive cells ameliorates noisy decision making in a schizophrenia mouse model (Neuroscience 2025) - "To functionally evaluate these predictions, we designed behavioral experiments using a two-choice probabilistic bandit task in MK-801-induced schizophrenia mouse models. Together, our study proposes a new framework for understanding the mechanism of clozapine, integrating quantitative behavioral analysis with molecular and cellular targeting, and may suggest novel intervention strategies for treatment-resistant schizophrenia. Ongoing experiments will further clarify the causal links between clozapine-responsive cell activation and behavioral rescue."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia • FOS

Delay discounting in NrCAM deficient mice under acute and chronic stress: beneficial effects of NMDA antagonist MK801 (Neuroscience 2025) - "Pharmacological manipulations support a differential role of NMDA and AMPA receptors in the DD paradigm, with beneficial roles of low-dose MK801 in reducing impulsive choice in NrCAM-deficient mice. Taken together, our results further support poor performance in various decision making tasks under stress and a link between NrCAM and vulnerability to stress-induced cognitive and behavioral dysfunctions."

Preclinical • CNS Disorders

Functional ultrasound mapping of medial septal nucleus deep brain stimulation in NMDA receptor hypofunction schizophrenia model (Neuroscience 2025) - "Adult mice received unilateral right-side intrahippocampal injections of either saline (n = 32) or MK-801 (n = 36), followed by MSN stimulation at either 7.7 Hz (theta) or 100 Hz (gamma) for 5 minutes via implanted electrodes...These results indicate that MSN stimulation can attenuate cerebrovascular flow and ROI function for certain ROIs, which depend on the stimulation paradigm. fUSI offers a robust platform to map neuromodulatory responses in neuropsychiatric disease models."

Late-breaking abstract • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Blood-brain barrier-permeable hdac3 selective inhibitor sp108 ameliorates hippocampal-dependent cognitive dysfunction in mam-induced animal model of schizophrenia (Neuroscience 2025) - "Behavioral paradigms assessing positive (pre-pulse inhibition, MK801-induced hyperlocomotion), negative (social interaction test), and cognitive (active avoidance task) symptoms in the next generation adult males were employed...SP108 elevated acetylated histone (H3K9ac) in CA2/3 regions and elevated BDNF-PSD95-Synapsin-1 in the isolated hippocampal tissues. These findings demonstrate that SP108-mediated HDAC3 inhibition improves hippocampal-dependent cognitive function in schizophrenia, underscoring its potential as a targeted therapeutic approach."

Preclinical • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • BDNF • DLG4 • HDAC3 • Napsin A

Differential Abuse Liability and Therapeutic Potential of Ketamine Enantiomers (Neuroscience 2025) - "Naltrexone significantly blunted this response at 1 and 0.5 mg/kg doses. MK-801 decreased (R)-ketamine infusions at 1 mg/kg dose...Our findings indicate that (R)-ketamine has reinforcing effects at sufficiently high doses and these effects may be due to its effects on the opioid system with different regional brain activity patterns than (S)-ketamine. (S)-ketamine decreases heroin seeking, suggesting potential for treating opioid use disorder."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Psychiatry • Substance Abuse

Machine Learning Enhanced Functional Ultrasound Imaging for predicting drug-induced brain activity changes (Neuroscience 2025) - "To address this limitation, we compared three machine learning approaches—convolutional neural network (CNN), support vector machine (SVM), and vision transformer (ViT)—combined with fUSI to analyze the pharmacodynamics of Dizocilpine (MK-801), a potent NMDA receptor antagonist, thereby eliminating ROI selection bias by processing the entire brain image directly...Ultimately, the combination of fUSI with machine learning techniques creates a powerful analytical framework for examining pharmacological mechanisms without relying on predefined ROIs, as this data-driven approach enables analysis of drug effects based on functional responses instead of anatomical assumptions. This methodological innovation can potentially reveal previously overlooked drug effects, accelerating drug development and enabling more comprehensive characterization of therapeutic compounds across both preclinical and clinical settings."

Machine learning • CNS Disorders

Top-down inputs show context-selective synchronization with V1 spiking following focal N-methyl-D-aspartate receptor blockade (Neuroscience 2025) - "Here, we sought to address this by measuring extracellular potentials (16-channel multielectrode probes) in the V1 and ACa of mice (n=10) during visual oddball sequences of full-field oriented square-wave grating stimuli (redundant, p=.9; deviant, p=.1) both before and after V1 NMDAR block via local application of MK-801...With respect to oddball versus control trials, the magnitude of MUA was significantly more modulated by the theta phase of frontal local field potentials from the anterior cingulate area (ACa; n=6). These data concord with past work demonstrating a suppressive input onto V1 from the ACa, potentially suggesting a bias of perceptual circuits towards internally-generated models when bottom-up signaling is disrupted."

Late-breaking abstract • CNS Disorders • Psychiatry • Schizophrenia

The influence of NMDAR antagonists on prefrontal cortex neuron activity during a touchscreen task of working memory in mice (Neuroscience 2025) - "We aimed to establish differences in firing rates between correct and incorrect trials during the maintenance phase, and to investigate how this changed after exposure to the NMDAR antagonists ketamine and MK-801.Male C57BL/6 mice (n=6) were trained to criterion on the TUNL task of working memory in automated touchscreen operant chambers, and then were implanted with a tetrode in the left mPFC. However, in our preliminary data we have found no changes in maintenance phase firing rate or relative changes from baseline to maintenance periods when comparing correct and incorrect trials across each treatment.We conclude there are overall no MUA differences between correct and incorrect trials during the maintenance phase of WM. While NMDAR antagonists increase mPFC activity during WM, most likely via disinhibiting neuronal firing, WM impairments induced by NMDAR antagonists may involve more complex mechanisms."

Preclinical • CNS Disorders

D2 receptor loss in cortical GABAergic interneurons increases putative glutamatergic neurons in the anterior cingulate cortex and reduces behavioral sensitivity to NMDA receptor antagonism. (Neuroscience 2025) - "In addition, GABAergic D2R-cKO mice exhibited significantly blunted locomotor activity to the NMDA receptor antagonist MK-801 compared to the control group (27-35% blunting in locomotion across multiple doses). Ongoing experiments include additional behavioral testing with memantine. Altogether, these results suggest that the early loss of D2Rs in inhibitory neurons can affect the development of cortical excitatory neurons and alter behavioral responses to NMDA receptor antagonists, providing a better understanding of D2R-mediated regulation of developing cortical circuitry and neurobehavioral trajectory."

CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia • DRD2

Intranasal MK-801 Attenuates Acute Neurochemical Alterations Induced by Concussion in a Rotational Weight-Drop Rat Model (Neuroscience 2025) - "These findings suggest that intranasally administered MK-801 rapidly reaches the brain and effectively suppresses the early excitotoxic surge of neurotransmitters following concussion. Intranasal delivery of NMDA antagonists may represent a promising strategy for acute neuroprotection in traumatic brain injury."

Preclinical • CNS Disorders • Vascular Neurology

Optogenetic cAMP production in mouse barrel cortex astrocytes induces PKA dependent long term potentiation (Neuroscience 2025) - "DdPAC-LTP and TBS-LTP induction were both blocked in the presence of MK801, an open channel blocker, and 5,7 DCK, an antagonist of the NMDAR Glycine/Serine site. DdPAC induced LTP was also seen in DdPAC expressing slices from IP3R2-/- mice. We conclude that astrocyte cAMP elevation can induce somatosensory cortex LTP in an astrocyte calcium independent manner, but utilising the same neuronal LTP induction mechanisms as synaptic theta burst stimulation."

Preclinical • CNS Disorders • DCK • GFAP

Spreading depolarizations in an ex vivo zebrafish model are preserved despite multi-channel inhibition: a comparative study with rodent slices (Neuroscience 2025) - "Using local KCl microinjection and DC local field potential recordings, we developed and tested a novel ex vivo protocol for studying SDs in the adult zebrafish optic tectum, characterizing SD initiation after the addition of TTX, MK-801 (or APV), NBQX, and NiCl₂. We also conducted comparable pharmacological experiments with a similar protocol in the CA1 of submerged hippocampal mouse slices and found that, in both models, although SD amplitude decreased, SDs persisted despite the combined inhibition of sodium, calcium, and glutamatergic channels, with no significant reduction in SD duration. These findings suggest that additional mechanisms beyond sodium, calcium, and glutamatergic signaling contribute to SD induction, lending additional evidence to the existence of other potential critical contributors to SD physiology, which we are actively exploring."

Preclinical • CNS Disorders • Epilepsy • Migraine • Vascular Neurology