2021
Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial
Patel KT, Stevens MC, Dunlap A, Gallagher A, O’Malley S, DeMartini K, Potenza MN, Krystal JH, Pearlson GD. Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial. Neuropsychopharmacology 2021, 47: 840-846. PMID: 34475522, PMCID: PMC8882177, DOI: 10.1038/s41386-021-01157-5.Peer-Reviewed Original ResearchConceptsProtein tyrosine kinasesSrc regulationSrc familyProtein kinaseTyrosine kinaseFyn kinaseSrc inhibitorSrc/FynDependent pathwayKinaseNMDAR upregulationNMDAR functionNMDA receptorsRegulationSaracatinibGluN2B subunitGlutamate receptorsFynInhibitorsReceptorsSubunitsN-methyl-D-aspartate (NMDA) glutamate receptorsPrevious evidenceSaracatinib Fails to Reduce Alcohol-Seeking and Consumption in Mice and Human Participants
Thompson SL, Gianessi CA, O'Malley SS, Cavallo DA, Shi JM, Tetrault JM, DeMartini KS, Gueorguieva R, Pittman B, Krystal JH, Taylor JR, Krishnan-Sarin S. Saracatinib Fails to Reduce Alcohol-Seeking and Consumption in Mice and Human Participants. Frontiers In Psychiatry 2021, 12: 709559. PMID: 34531767, PMCID: PMC8438169, DOI: 10.3389/fpsyt.2021.709559.Peer-Reviewed Original ResearchNMDA receptorsSrc/FynAlcohol consumptionEffect of saracatinibVehicle 2 hChronic alcohol useDays of treatmentDSM-IV criteriaMore effective treatmentsNumber of drinksGlutamatergic systemAdditional drinkAlcohol drinkingAdditional dosesEthanol exposureEffective treatmentNR2B subunitAlcohol abuseHuman studiesPriming drinkAlcohol cravingSaracatinibDrinking paradigmNovel pharmacotherapeuticsHuman participants
2016
The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models
Khlestova E, Johnson JW, Krystal JH, Lisman J. The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models. Journal Of Neuroscience 2016, 36: 11151-11157. PMID: 27807157, PMCID: PMC5148234, DOI: 10.1523/jneurosci.1203-16.2016.Peer-Reviewed Original ResearchConceptsNMDAR antagonistsNMDA receptor hypofunction hypothesisDifferent NMDAR subtypesHealthy human subjectsSymptoms of schizophreniaPsychotogenic effectsNMDA receptorsNMDAR subtypesSchizophrenia modelKetamine's abilityNegative symptomsKetamineMultiple subtypesPsychotic statesPreferential involvementSchizophreniaAntagonistGluN2CSubtypesReceptorsEEG powerHuman subjectsNMDARSymptomsΔ oscillations
2015
N‐Methyl‐d‐Aspartate Receptor Antagonism has Differential Effects on Alcohol Craving and Drinking in Heavy Drinkers
Krishnan‐Sarin S, O'Malley SS, Franco N, Cavallo DA, Morean M, Shi J, Pittman B, Krystal JH. N‐Methyl‐d‐Aspartate Receptor Antagonism has Differential Effects on Alcohol Craving and Drinking in Heavy Drinkers. Alcohol Clinical And Experimental Research 2015, 39: 300-307. PMID: 25664775, PMCID: PMC4331214, DOI: 10.1111/acer.12619.Peer-Reviewed Original ResearchConceptsAlcohol drinkingFamily historyHeavy drinkersAlcohol cravingN-methyl-D-aspartate receptor antagonistN-methyl-D-aspartate receptor antagonismAlcohol cue-induced cravingEffects of FHHigher baseline levelsPresence of impulsivityAlcohol use disorderCue-induced cravingAlcohol-induced stimulationReceptor antagonismReceptor antagonistPriming doseNMDA receptorsUse disordersMemantineBaseline levelsModulatory influencePotential efficacyAlcohol accessDrinkersEighth day
2013
Glutamatergic targets for new alcohol medications
Holmes A, Spanagel R, Krystal JH. Glutamatergic targets for new alcohol medications. Psychopharmacology 2013, 229: 539-554. PMID: 23995381, PMCID: PMC3811052, DOI: 10.1007/s00213-013-3226-2.Peer-Reviewed Original ResearchConceptsGlutamate systemGlycineB siteAlcohol-related behaviorsNMDA receptorsAlcohol abuseAlcohol consumptionN-methyl-D-aspartate receptorsChronic alcohol exposureElevated extracellular glutamatePathophysiology of alcoholismAMPA receptor subunitsAlcohol use disorderNovel pharmacotherapeutic approachesEffects of alcoholAlcohol medicationsBlocking NMDAHyperglutamatergic stateMetabotropic receptorsPharmacotherapeutic approachesAlcohol exposureExcess glutamateExtracellular glutamateGlutamate receptorsPreclinical studiesKainate 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
2008
Ethanol-like effects of thiopental and ketamine in healthy humans
Dickerson D, Pittman B, Ralevski E, Perrino A, Limoncelli D, Edgecombe J, Acampora G, Krystal J, Petrakis I. Ethanol-like effects of thiopental and ketamine in healthy humans. Journal Of Psychopharmacology 2008, 24: 203-211. PMID: 19028835, PMCID: PMC4484757, DOI: 10.1177/0269881108098612.Peer-Reviewed Original ResearchConceptsEthanol-like effectsEthanol-related effectsNMDA receptor antagonistBlock NMDA receptorsNMDA receptor antagonismSeparate test daysGamma-aminobutyric acidReceptor antagonismSubanesthetic dosesReceptor antagonistNMDA receptorsFamily historyEthanol intoxicationHealthy humansPharmacological agentsEthanol effectsKetamineReceptor activityReceptor functionLarger studyBehavioral effectsThiopentalIntoxicationSubjective intoxicationTest dayRelationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy—a [123I]CNS-1261 SPET study
Stone JM, Erlandsson K, Arstad E, Squassante L, Teneggi V, Bressan RA, Krystal JH, Ell PJ, Pilowsky LS. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy—a [123I]CNS-1261 SPET study. Psychopharmacology 2008, 197: 401-408. PMID: 18176855, DOI: 10.1007/s00213-007-1047-x.Peer-Reviewed Original ResearchMeSH KeywordsAdultBrief Psychiatric Rating ScaleDose-Response Relationship, DrugGuanidinesHumansInfusions, IntravenousIodine RadioisotopesKetamineMalePrefrontal CortexPsychoses, Substance-InducedReceptors, N-Methyl-D-AspartateSchizophreniaSingle-Blind MethodTomography, Emission-Computed, Single-PhotonConceptsBrief Psychiatric Rating ScaleVolume of distributionNMDA receptorsPsychotic symptomsN-methyl-D-aspartate receptorsKetamine-induced psychotic symptomsSingle photon emission tomographyNMDA receptor bindingEffects of ketamineNegative subscaleHealthy human controlsPsychiatric Rating ScaleNegative psychotic symptomsInferior frontal cortexKetamine administrationBolus infusionHealthy controls
2007
Absence of Significant Interactive Effects of High‐Dose d‐Cycloserine and Ethanol in Healthy Human Subjects: Preliminary Insights Into Ethanol Actions at the GlycineB Site of NMDA Glutamate Receptors
Trevisan L, Petrakis IL, Pittman B, Gueorguieva R, D’Souza D, Perry E, Limoncelli D, Krystal JH. Absence of Significant Interactive Effects of High‐Dose d‐Cycloserine and Ethanol in Healthy Human Subjects: Preliminary Insights Into Ethanol Actions at the GlycineB Site of NMDA Glutamate Receptors. Alcohol Clinical And Experimental Research 2007, 32: 36-42. PMID: 18028532, DOI: 10.1111/j.1530-0277.2007.00543.x.Peer-Reviewed Original ResearchConceptsCo-agonist siteHealthy human subjectsEthanol administrationD-cycloserineHigh-dose d-cycloserineAlcohol levelsReceptor functionPlacebo 4 hoursDouble-blind conditionsNMDA receptor functionNMDA glutamate receptorsMild sedative effectDoses of ethanolGlutamate receptor functionBreath alcohol levelsHuman subjectsVerbal fluencyGlycineB siteGroups of subjectsEthanol antagonismCombination of ethanolSedative effectsNMDA receptorsClinical significanceGlutamate receptorsThe NMDA receptor as a therapeutic target in major depressive disorder.
Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS & Neurological Disorders - Drug Targets 2007, 6: 101-15. PMID: 17430148, DOI: 10.2174/187152707780363267.Peer-Reviewed Original ResearchConceptsMajor depressive disorderNMDA receptorsDepressive disorderNovel antidepressant medicationsCognitive side effectsPotential of drugsAntidepressant medicationAntidepressant propertiesSuch medicationsGlutamatergic neurotransmissionGlutamate receptorsPreclinical studiesPsychotomimetic propertiesSide effectsTherapeutic targetAnimal modelsUseful agentNeurotransmissionReceptorsLines of evidenceMedicationsDisordersDrugsCurrent knowledgeDepression
2005
Impact of Schizophrenia and Chronic Antipsychotic Treatment on [123I]CNS-1261 Binding to N-Methyl-D-Aspartate Receptors In Vivo
Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ, Pilowsky LS. Impact of Schizophrenia and Chronic Antipsychotic Treatment on [123I]CNS-1261 Binding to N-Methyl-D-Aspartate Receptors In Vivo. Biological Psychiatry 2005, 58: 41-46. PMID: 15992521, DOI: 10.1016/j.biopsych.2005.03.016.Peer-Reviewed Original ResearchConceptsHealthy control subjectsTypical antipsychoticsControl subjectsN-methyl-D-aspartate receptor functionN-methyl-D-aspartate receptorsAntipsychotic drug discoveryChronic antipsychotic treatmentDrug-free patientsImpact of schizophreniaNMDA receptor activityHealthy normal volunteersClozapine treatmentAntipsychotic treatmentGlutamatergic systemPatient groupAntipsychotic drugsNonsignificant reductionNMDA receptorsNormal volunteersSchizophrenia patientsControl groupReceptor activityBrain regionsReceptor functionTomography radiotracer
2003
Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients
Krystal JH, Petrakis IL, Limoncelli D, Webb E, Gueorgueva R, D'Souza DC, Boutros NN, Trevisan L, Charney DS. Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients. Neuropsychopharmacology 2003, 28: 2020-2028. PMID: 12888778, DOI: 10.1038/sj.npp.1300252.Peer-Reviewed Original ResearchConceptsEthanol-dependent patientsNMDA receptor antagonistReceptor antagonistEthanol dependenceN-methyl-D-aspartate (NMDA) glutamate receptorsDouble-blind studySelective NMDA receptor antagonistNMDA receptor functionAlcohol-dependent patientsHealthy comparison subjectsTreatment of alcoholismHealthy comparison groupExecutive cognitive functionKetamine infusionKetamine 0.5NMDA receptorsGlutamate receptorsComparison subjectsPatientsAmnestic effectsRandomized orderReceptor functionCognitive functionAntagonist responseAntagonist
2001
NMDA receptor regulation of memory and behavior in humans
Newcomer J, Krystal J. NMDA receptor regulation of memory and behavior in humans. Hippocampus 2001, 11: 529-542. PMID: 11732706, DOI: 10.1002/hipo.1069.Peer-Reviewed Original ResearchConceptsNMDA receptor hypofunctionReceptor hypofunctionN-methyl-D-aspartate (NMDA) receptor hypofunctionNMDA receptor antagonist drugsNMDA receptor systemAge-related decreaseNMDA receptor regulationReceptor antagonist drugsClinical syndromeNeuropathological featuresNMDA antagonistsNMDA receptorsNeurotoxic processesAntagonist drugsAdult brainHypofunctionBehavioral dysfunctionHuman studiesRange of effectsReceptor regulationReceptor systemBrain functionBrain ageAdverse effectsDisease conditionsAttenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men: Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists
Krupitsky E, Burakov A, Romanova T, Grinenko N, Grinenko A, Fletcher J, Petrakis I, Krystal J. Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men: Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists. Neuropsychopharmacology 2001, 25: 936-947. PMID: 11750186, DOI: 10.1016/s0893-133x(01)00346-3.Peer-Reviewed Original ResearchConceptsVoltage-sensitive calcium channelsL-type voltage-sensitive calcium channelsKetamine effectsStimulant effectsCalcium channelsDouble-blind placebo-controlled studyN-methyl-D-aspartate (NMDA) glutamate receptorsL-type calcium channel antagonistL-type VSCC antagonistBehavioral effectsTransient behavioral effectsPlacebo-controlled studyCalcium channel antagonistsImproved memory functionInteraction of NMDAAspects of schizophreniaNimodipine pretreatmentVSCC antagonistsVerbal fluency impairmentPatient groupKetamine responseChannel antagonistsNMDA antagonistsNMDA receptorsEthanol intoxication