2025
Hippocampal ensembles regulate circuit-induced relapse of extinguished fear
Hassell J, Arellano Perez A, Vasudevan K, Ressler R, Garcia G, Parr M, Vierkant V, Bayer H, Maren S. Hippocampal ensembles regulate circuit-induced relapse of extinguished fear. Molecular Psychiatry 2025, 1-10. PMID: 40413310, DOI: 10.1038/s41380-025-03064-3.Peer-Reviewed Original ResearchPost-traumatic stress disorderContextual fear memoryFear memoryExtinction learningFear conditioningConditioned stimulusExcitatory DREADDsFormation of contextual fear memoryChemogenetic reactivationRelapse of fearAuditory conditioned stimulusIntra-hippocampal infusionThalamic nucleus reuniensAuditory fear conditioningNMDA receptor antagonistExtinguished CSBehavioral therapyStress disorderNucleus reuniensHippocampal ensemblesReuniensReceptor antagonistHPC neuronsMemoryDREADDsNeuroprotective Strategies in Coronary Artery Disease Interventions
Fatima M, Bazarbaev A, Rana A, Khurshid R, Effiom V, Bajwa N, Nasir A, Candelario K, Tabraiz S, Colon S, Lee C, Dankwa S, Hameed I. Neuroprotective Strategies in Coronary Artery Disease Interventions. Journal Of Cardiovascular Development And Disease 2025, 12: 143. PMID: 40278202, PMCID: PMC12027976, DOI: 10.3390/jcdd12040143.Peer-Reviewed Original ResearchCoronary Artery Bypass GraftingDeep hypothermic circulatory arrestNeurological complicationsNerve injuryNeuroprotective strategiesOff-pump coronary artery bypass graftingHybrid revascularizationHypothermic circulatory arrestCranial nerve injuryNMDA receptor antagonistHigh-risk patientsEndoscopic coronary artery bypassCoronary artery bypassPeripheral nerve injuryArtery Bypass GraftingCerebral perfusion monitoringBloodless surgical fieldCoronary artery interventionRisk of strokeEmbolic protection devicesAntiplatelet administrationAortic manipulationReceptor antagonistCirculatory arrestTherapeutic hypothermiaMEMORY RELATED STRUCTURAL AND FUNCTIONAL NEURAL CHANGES FOLLOWING A SINGLE INFUSION OF KETAMINE IN PTSD
Harpaz-Rotem *, Duek O, Korem N, Krystal J. MEMORY RELATED STRUCTURAL AND FUNCTIONAL NEURAL CHANGES FOLLOWING A SINGLE INFUSION OF KETAMINE IN PTSD. The International Journal Of Neuropsychopharmacology 2025, 28: i38-i38. PMCID: PMC11814760, DOI: 10.1093/ijnp/pyae059.066.Peer-Reviewed Original ResearchPost-retrieval extinctionInfusion of ketamineIntravenous infusion of ketamineTrauma memoriesTraumatic memoriesFear responsesSs' responsesAssociated with decreased connectivityAmygdala-vmPFC connectivityTrauma-focused psychotherapyTreatment of PTSDNMDA receptor antagonistPre-post treatmentAmygdala activationLower amygdalaReconsolidation windowUncinate fasciculusAssessed before treatmentKetamine administrationMemory learningNaturalistic stimuliLabile stateAmygdalaPTSDExtinction process
2023
Long term structural and functional neural changes following a single infusion of Ketamine in PTSD
Duek O, Korem N, Li Y, Kelmendi B, Amen S, Gordon C, Milne M, Krystal J, Levy I, Harpaz-Rotem I. Long term structural and functional neural changes following a single infusion of Ketamine in PTSD. Neuropsychopharmacology 2023, 48: 1648-1658. PMID: 37270621, PMCID: PMC10517133, DOI: 10.1038/s41386-023-01606-3.Peer-Reviewed Original ResearchConceptsKetamine recipientsSingle infusionMain study outcomeTiming of administrationEnd of treatmentNMDA receptor antagonistFunctional neural changesFrequency of administrationSignificant clinical implicationsTrauma-focused psychotherapyBrief exposure therapyAmygdala-vmPFC connectivityPost-retrieval extinctionKetamine doseKetamine administrationReceptor antagonistTrauma scriptsNeural changesClinical implicationsDecreased connectivityExposure therapyKetamineTrauma memoriesStudy outcomesUncinate fasciculus
2022
Biomarkers of ketamine's antidepressant effect: An umbrella review
Meshkat S, Ho R, Cao B, Teopiz K, Rosenblat J, Rhee T, Di Vincenzo J, Ceban F, Jawad M, McIntyre R. Biomarkers of ketamine's antidepressant effect: An umbrella review. Journal Of Affective Disorders 2022, 323: 598-606. PMID: 36521662, DOI: 10.1016/j.jad.2022.12.021.Peer-Reviewed Original ResearchConceptsKetamine's antidepressant effectsAntidepressant effectsUmbrella reviewMajor depressive disorder (MDD) pathogenesisRapid acting antidepressant (RAAD) effectsMechanistically relevant biomarkersPotential peripheral biomarkerTreatment-resistant patientsAnti-inflammatory effectsNMDA receptor antagonistReal-world populationTreatment response predictionInflammatory markersPeripheral biomarkersKetamine actionReceptor antagonistSymptom deteriorationClinical utilityNeuroimaging biomarkersDisorder pathogenesisSynaptic plasticityCingulate cortexSystematic reviewKetamineFunctional connectivity
2020
Chapter Four Clinical overview of NMDA-R antagonists and clinical practice
Davoudian PA, Wilkinson ST. Chapter Four Clinical overview of NMDA-R antagonists and clinical practice. Advances In Pharmacology 2020, 89: 103-129. PMID: 32616204, DOI: 10.1016/bs.apha.2020.04.004.ChaptersConceptsNMDA receptor antagonistReceptor antagonistGlutamatergic systemClinical trialsPathophysiology of depressionLevels of monoaminesNMDA-R antagonistsTreatment of depressionRole of glutamatePatient's therapeutic responseRecent FDA approvalIntranasal esketamineMonoamine hypothesisPathophysiological mechanismsClinical overviewTherapeutic responseCurrent treatmentClinical practiceTranslational studiesMental illnessFDA approvalNeural circuitsAntagonistDepressionPotential mechanismsImpaired neuronal and astroglial metabolic activity in chronic unpredictable mild stress model of depression: Reversal of behavioral and metabolic deficit with lanicemine
Mishra PK, Adusumilli M, Deolal P, Mason GF, Kumar A, Patel AB. Impaired neuronal and astroglial metabolic activity in chronic unpredictable mild stress model of depression: Reversal of behavioral and metabolic deficit with lanicemine. Neurochemistry International 2020, 137: 104750. PMID: 32360130, DOI: 10.1016/j.neuint.2020.104750.Peer-Reviewed Original ResearchConceptsChronic unpredictable mild stressCUMS micePrefrontal cortexChronic unpredictable mild stress (CUMS) modelNeurotransmitter cyclingThree-compartment metabolic modelUnpredictable mild stressCause of disabilityNMDA receptor antagonistPotential therapeutic roleMajor depressive disorderAstrocytic TCA cycleNeural metabolic activityMetabolic activityGABAergic neuronsInhibitory neurotransmissionReceptor antagonistSwim testSucrose preferenceC57BL6 miceDepressive disorderTherapeutic roleChronic depressionGlutamatergic pathwaysMetabolic deficitsGABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. Journal Of Clinical Investigation 2020, 130: 1336-1349. PMID: 31743111, PMCID: PMC7269589, DOI: 10.1172/jci130808.Peer-Reviewed Original ResearchConceptsRapid antidepressant actionsAntidepressant actionGABA interneuronsMedial prefrontal cortexCell-specific knockdownPrinciple neuronsPrefrontal cortexDeletion of GluN2BSingle subanesthetic doseBehavioral actionsAction of ketamineNMDA receptor antagonistExcitatory postsynaptic currentsCellular triggersMajor unmet needKetamine's rapid antidepressant actionsGABA subtypeGluN2B-NMDARsSST interneuronsPostsynaptic currentsReceptor antagonistDepressed patientsSubanesthetic doseExtracellular glutamateMood disordersKetamine induces immediate and delayed alterations of OCD-like behavior
Thompson SL, Welch AC, Iourinets J, Dulawa SC. Ketamine induces immediate and delayed alterations of OCD-like behavior. Psychopharmacology 2020, 237: 627-638. PMID: 31927606, DOI: 10.1007/s00213-019-05397-8.Peer-Reviewed Original ResearchConceptsOCD-like behaviorPrepulse inhibitionTherapeutic effectH postinjectionNoncompetitive NMDA receptor antagonistOCD patientsAnti-OCD effectsRationaleObsessive-compulsive disorderNMDA receptor antagonistRapid therapeutic effectPretreatment time pointsAcute ketaminePharmacological monotherapyKetamine pretreatmentKetamine treatmentPPI deficitsReuptake inhibitorsReceptor antagonistLow doseMin postinjectionPsychiatric disordersDelayed alterationsResponse rateHigh dosesKetamine
2019
N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects
Fogaça MV, Fukumoto K, Franklin T, Liu RJ, Duman CH, Vitolo OV, Duman RS. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology 2019, 44: 2230-2238. PMID: 31454827, PMCID: PMC6898593, DOI: 10.1038/s41386-019-0501-x.Peer-Reviewed Original ResearchConceptsNovelty-suppressed feeding testMedial prefrontal cortexD-methadoneNMDA receptor antagonistAntidepressant actionPhospho-p70S6 kinaseReceptor antagonistN-methyl-D-aspartate receptorsNoncompetitive NMDA receptor antagonistTreatment-resistant patientsChronic unpredictable stressRapid antidepressant actionsDissociative side effectsPrimary cortical culturesMeasures of anhedoniaKetamine inducesAvailable antidepressantsTolerability profileAntidepressant effectsBDNF releaseAntidepressant responseResistant patientsFavorable safetySingle doseCortical culturesDoes Self-Reported or Behavioral Impulsivity Predict Subjective Response to Low-Dose Alcohol?
Berey BL, Leeman RF, Pittman B, Franco N, Krishnan-Sarin S. Does Self-Reported or Behavioral Impulsivity Predict Subjective Response to Low-Dose Alcohol? Alcohol And Alcoholism 2019, 54: 180-187. PMID: 30649160, PMCID: PMC6476413, DOI: 10.1093/alcalc/agy092.Peer-Reviewed Original ResearchConceptsLow-dose alcoholBlood alcohol concentrationAlcohol use disorderHeavy drinkersSubjective responsesTrend-level predictorNMDA receptor antagonistBiphasic Alcohol Effects ScaleAlcohol administration studyIndependent predictorsReceptor antagonistRisk factorsUse disordersSubjective stimulationGo/No-Go taskMore impulsive individualsHigh dosesEffects ScaleSedationAlcohol useSubjective effectsAdministration studiesImpulsivity measuresBarratt Impulsiveness ScaleDrinking occasions
2018
Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)
Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular Psychiatry 2018, 25: 1592-1603. PMID: 30283029, PMCID: PMC6447473, DOI: 10.1038/s41380-018-0256-5.Peer-Reviewed Original ResearchConceptsTreatment-resistant depressionSingle doseActive placeboSubanesthetic dosesIntravenous ketamineAdult treatment-resistant depressionTransient blood pressure elevationTransient antidepressant effectsBlood pressure elevationPlacebo-controlled studyDose-ranging trialInfusion of ketaminePrimary outcome measureAbility of ketamineCurrent depressive episodeSingle intravenous doseNMDA receptor antagonistTime interaction effectsMeaningful efficacyAntidepressant doseGreater dissociative symptomsAdjunctive therapyAntidepressant effectsEligible subjectsSecondary outcomes2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE
Krystal J. 2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE. Schizophrenia Bulletin 2018, 44: s1-s1. PMCID: PMC5887654, DOI: 10.1093/schbul/sby014.001.Peer-Reviewed Original ResearchNMDA glutamate receptorsNMDA receptor antagonistCortical functional connectivityPathophysiology of schizophreniaReceptor antagonistTranslational neuroscience perspectiveGlutamate receptorsHealthy humansAnimal modelsSchizophrenia patientsMemory impairmentNeuropsychiatric disordersSynaptic signalingFunctional connectivityNovel therapeuticsSchizophreniaDisordersPresentationPatientsPathophysiologyDysfunctionKetamineAntagonistSymptomsAbnormalities
2016
Ketamine accelerates fear extinction via mTORC1 signaling
Girgenti MJ, Ghosal S, LoPresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiology Of Disease 2016, 100: 1-8. PMID: 28043916, PMCID: PMC5907920, DOI: 10.1016/j.nbd.2016.12.026.Peer-Reviewed Original ResearchConceptsPost-traumatic stress disorderMedial prefrontal cortexTreatment of PTSDFear conditioningRetrieval of extinctionExpression of extinctionActivity-dependent effectsTraumatic memoriesStress disorderExtinction exposurePTSD patientsPrefrontal cortexEffects of ketamineGlutamate NMDA receptor antagonistSymptom severityConditioningInfusion of ketamineExtinctionCuesRodent modelsMemoryKetamine administrationReceptor antagonistPresent studyNMDA receptor antagonist
2013
Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions
Corlett PR, Cambridge V, Gardner JM, Piggot JS, Turner DC, Everitt JC, Arana FS, Morgan HL, Milton AL, Lee JL, Aitken MR, Dickinson A, Everitt BJ, Absalom AR, Adapa R, Subramanian N, Taylor JR, Krystal JH, Fletcher PC. Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions. PLOS ONE 2013, 8: e65088. PMID: 23776445, PMCID: PMC3680467, DOI: 10.1371/journal.pone.0065088.Peer-Reviewed Original ResearchConceptsMemory strengthMemory reconsolidationIndividual brain responsesError-dependent learningPsychotogenic effectsSubsequent memoryFear memoryBizarre beliefsBrain responsesDelusional beliefsPrediction errorImpact of ketamineIndividual vulnerabilityBrain signalsSubject studyReconsolidationIndependent samplesLearning procedureMemoryKetamine effectsDelusionsBeliefsPlacebo administrationPsychosisNMDA receptor antagonistConnectivity, Pharmacology, and Computation: Toward a Mechanistic Understanding of Neural System Dysfunction in Schizophrenia
Anticevic A, Cole MW, Repovs G, Savic A, Driesen NR, Yang G, Cho YT, Murray JD, Glahn DC, Wang XJ, Krystal JH. Connectivity, Pharmacology, and Computation: Toward a Mechanistic Understanding of Neural System Dysfunction in Schizophrenia. Frontiers In Psychiatry 2013, 4: 169. PMID: 24399974, PMCID: PMC3871997, DOI: 10.3389/fpsyt.2013.00169.Peer-Reviewed Original ResearchNMDA receptor antagonistFunctional neuroimaging toolsFunctional imaging studiesNeural system dysfunctionsRecent neuroimaging studiesKetamine administrationRecent findingsPharmacological treatmentSynaptic dysfunctionReceptor antagonistSystem dysfunctionPathophysiologic hypothesesBipolar illnessHealthy subjectsResting-state neuroimagingHealthy volunteersClinical investigationHealthy humansPsychiatric disordersCardinal featuresPharmacological manipulationPsychiatric conditionsLocal circuitsImaging studiesNeuropsychiatric diseases
2012
Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans
Moghaddam B, Krystal JH. Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans. Schizophrenia Bulletin 2012, 38: 942-949. PMID: 22899397, PMCID: PMC3446228, DOI: 10.1093/schbul/sbs075.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric RegulationAnimalsAntipsychotic AgentsBrief Psychiatric Rating ScaleCerebral CortexDisease Models, AnimalDopamineEmotionsGlutamic AcidHumansKetamineNeurosciencesPhencyclidinePsychoses, Substance-InducedReceptor, Metabotropic Glutamate 5Receptors, Dopamine D2Receptors, Metabotropic GlutamateReceptors, N-Methyl-D-AspartateSchizophreniaSynapsesTranslational Research, BiomedicalConceptsNMDA receptor antagonistReceptor antagonistDopamine hypothesisN-methyl-D-aspartate receptor antagonistGlutamate synaptic functionTranslational neuroscience studiesTreatment of schizophreniaPathophysiology of schizophreniaPotential treatment targetPotential new targetsDopamine antagonistsCortical functionAnimal studiesTreatment targetsClinical testingSynaptic functionAntagonistTranslational toolSchizophreniaTranslational research fundingTranslational researchPotential mechanismsNew targetsAngel dustSystems neuroscienceMemantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism
Jamadar S, DeVito EE, Jiantonio RE, Meda SA, Stevens MC, Potenza MN, Krystal JH, Pearlson GD. Memantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism. Psychopharmacology 2012, 222: 129-140. PMID: 22311382, PMCID: PMC3674025, DOI: 10.1007/s00213-011-2628-2.Peer-Reviewed Original ResearchConceptsNMDA receptor antagonistFamily historyFHN subjectsReceptor antagonistFHP subjectsN-methyl-D-aspartate receptor functionReceptor functionIdentical-appearing placeboEffects of memantineFMRI activityNMDA receptor functionCorrect rejectsSingle doseMemantineGo/No-Go taskSeparate daysTemporal regionsCingulate activation
2011
Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure. Biological Psychiatry 2011, 69: 754-761. PMID: 21292242, PMCID: PMC3068225, DOI: 10.1016/j.biopsych.2010.12.015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBehavior, AnimalBlotting, WesternChoice BehaviorDendritic SpinesElectrophysiologyExcitatory Amino Acid AntagonistsKetamineNeuronsPhenolsPiperidinesPrefrontal CortexRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSignal TransductionSirolimusStress, PhysiologicalStress, PsychologicalSynapsesSynaptic TransmissionConceptsGlutamate N-methyl-d-aspartate (NMDA) receptor antagonistN-methyl-D-aspartate receptor antagonistNMDA receptor antagonistReceptor antagonistLayer V pyramidal neuronsChronic unpredictable stress modelMammalian targetStress exposureDepressant-like behaviorLong-term stress exposurePathophysiology of depressionRapid antidepressant actionsSelective NMDA receptorChronic stress exposurePrefrontal cortex neuronsAntidepressant actionAcute treatmentChronic administrationSynaptic deficitsPyramidal neuronsSpine densityRo 25Cortex neuronsFunctional deficitsNMDA receptors
2010
Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence
Krystal JH, Petrakis IL, Limoncelli D, Nappi SK, Trevisan L, Pittman B, D'Souza DC. Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence. Neuropsychopharmacology 2010, 36: 701-710. PMID: 21124304, PMCID: PMC3055693, DOI: 10.1038/npp.2010.203.Peer-Reviewed Original ResearchConceptsNMDA receptor functionAlcohol-dependent patientsHuman alcohol dependenceAntagonist-like effectsReceptor functionReceptor antagonistDCS effectsD-cycloserineAlcohol-like effectsAlcohol dependenceNMDA glutamate receptor functionN-methyl-D-aspartate (NMDA) glutamate receptor antagonistStandard alcohol drinksGlutamate receptor antagonistsChronic alcohol consumptionDouble-blind conditionsNMDA receptor antagonistAlcohol-dependent menGlutamate receptor functionAlcohol-dependent animalsPlasma levelsGlycine administrationGlycine levelsNMDA receptorsCoagonist site
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