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
Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change
Anticevic A, Hu X, Xiao Y, Hu J, Li F, Bi F, Cole MW, Savic A, Yang GJ, Repovs G, Murray JD, Wang XJ, Huang X, Lui S, Krystal JH, Gong Q. Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change. Journal Of Neuroscience 2015, 35: 267-286. PMID: 25568120, PMCID: PMC4287147, DOI: 10.1523/jneurosci.2310-14.2015.Peer-Reviewed Original ResearchConceptsEarly course schizophreniaFunctional connectivityPrefrontal cortexImmediate symptom improvementSevere mental illnessEarly course patientsHealthy human subjectsHuman subjectsWhole-brain levelFunctional connectivity patternsResting-state fMRIIllness onsetSymptom improvementChronic illnessFunctional impairmentTherapeutic implicationsPFC connectivityOverall connection strengthMental illnessLongitudinal progressionLongitudinal changesSchizophrenia studiesSchizophreniaDiagnostic classificationPatients
2013
Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans
Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC, Gueorguieva R, He G, Ramachandran R, Suckow RF, Anticevic A, Morgan PT, Krystal JH. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Molecular Psychiatry 2013, 18: 1199-1204. PMID: 23337947, PMCID: PMC3646075, DOI: 10.1038/mp.2012.194.Peer-Reviewed Original ResearchConceptsFunctional connectivityNegative symptomsGamma-aminobutyric acid (GABA) neuronsNMDA receptor antagonist ketamineAspartate glutamate receptor antagonistContinuous ketamine infusionGlutamate receptor antagonistsNMDA-R antagonistsCortical functional connectivityNMDA-R antagonist ketamineSchizophrenia-like symptomsHealthy human subjectsNegative Syndrome ScaleBrain functional connectivityPrimary samplesRegion-specific mannerFunctional magnetic resonanceKetamine infusionReceptor antagonistPathological increaseSyndrome ScaleSymptomsPreclinical researchKetamineBrain oscillations
2010
The interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects
Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Machado-de-Sousa JP, Abrão J, Crippa JA, McGuire P, Krystal JH, Baker GB, Zuardi AW. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Progress In Neuro-Psychopharmacology And Biological Psychiatry 2010, 35: 198-202. PMID: 21062637, DOI: 10.1016/j.pnpbp.2010.11.002.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScaleHealthy human subjectsGlutamate receptor systemMale healthy volunteersNMDA receptor antagonistEffects of ketamineTreatment of schizophreniaPsychiatric Rating ScaleHuman subjectsWeak partial agonistNon-significant trendKetamine administrationReceptor antagonistEndocannabinoid systemHealthy volunteersPartial agonistActivation subscalePsychiatric conditionsKetamineRandomized orderReceptor systemBehavioral effectsRating ScaleCannabidiolPreliminary evidence
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 receptorsPsychiatric safety of ketamine in psychopharmacology research
Perry EB, Cramer JA, Cho HS, Petrakis IL, Karper LP, Genovese A, O’Donnell E, Krystal JH, D’Souza D. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology 2007, 192: 253-260. PMID: 17458544, DOI: 10.1007/s00213-007-0706-2.Peer-Reviewed Original ResearchConceptsSubanesthetic dosesHealthy human subjectsKetamine administrationClinical research programHuman subjectsTest sessionsPsychotic spectrum disordersPsychiatric safetyResidual sequelaePlacebo infusionIntravenous infusionKetamine effectsPsychopharmacology studiesResultsFour hundredAdverse reactionsObjectiveTo reportHealthy subjectsStudy participationClinical investigationHealthy humansSide effectsKetamineInfusionDosesAdministration
2006
Cerebral Metabolic Effects of Intravenous Glycine in Healthy Human Subjects
Neumeister A, Carson R, Henry S, Planeta-Wilson B, Binneman B, Maguire RP, Luckenbaugh DA, D'Souza C, Krystal JH, Frost JJ. Cerebral Metabolic Effects of Intravenous Glycine in Healthy Human Subjects. Journal Of Clinical Psychopharmacology 2006, 26: 595-599. PMID: 17110816, DOI: 10.1097/01.jcp.0000245558.14284.aa.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntipsychotic AgentsBehaviorBrainBrain MappingCluster AnalysisCross-Over StudiesDouble-Blind MethodFemaleFluorodeoxyglucose F18GlycineHumansInfusions, IntravenousMagnetic Resonance ImagingMaleNeuropsychological TestsPositron-Emission TomographyRadiopharmaceuticalsReference ValuesSerineConceptsN-methyl-D-aspartate receptor functionReceptor functionRegional cerebral metabolic rateAdministration of glycineCerebral metabolic effectsMagnetic resonance imaging studyPositron emission tomography studyHealthy control subjectsNMDA receptor functionCerebral metabolic rateEmission tomography studiesTest dayHealthy human subjectsResonance imaging studySignificant reductionPositron emission tomographyDorsolateral prefrontal cortexIntravenous glycinePlacebo infusionCerebral metabolismPatient populationControl subjectsGlycine administrationGlycine infusionIntravenous administrationPotentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism
Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D'Souza DC. Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism. Neuropsychopharmacology 2006, 31: 1793-1800. PMID: 16395307, DOI: 10.1038/sj.npp.1300994.Peer-Reviewed Original ResearchConceptsNMDA glutamate receptorsNMDA receptor antagonismKetamine doseReceptor antagonismGlutamate receptorsKetamine effectsProtective effectPlacebo-controlled human laboratory studyOpiate receptor antagonismEfficacy of naltrexoneDose-related fashionNMDA receptor antagonist effectsReceptor antagonist effectsTotal PANSS scoreHuman laboratory studiesPharmacotherapy of alcoholismTreatment of alcoholismHealthy human subjectsHigher ketamine doseNegative Syndrome ScaleLower ketamine doseSignificant behavioral effectsSubanesthetic dosePANSS scoresEthanol drink
2005
Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine
Cho HS, D’Souza D, Gueorguieva R, Perry EB, Madonick S, Karper LP, Abi-Dargham A, Belger A, Abi-Saab W, Lipschitz D, Bennet A, Seibyl JP, Krystal JH. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology 2005, 179: 136-143. PMID: 15682309, DOI: 10.1007/s00213-004-2066-5.Peer-Reviewed Original ResearchConceptsHealthy human subjectsBehavioral sensitizationReceptor antagonistN-methyl-D-aspartate (NMDA) glutamate receptor antagonistBehavioral effectsHuman subjectsGlutamate receptor antagonistsNMDA receptor antagonistConclusionsThe current dataEvidence of sensitizationRetrospective studyKetamine administrationOutcome measuresNegative symptomsObjectivesThe purposePrevious exposureFirst exposureKetamineSensitizationAntagonistExposurePerceptual alterationsCurrent dataSeparate studiesSubjects
2004
Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects
Krystal JH, Abi-Saab W, Perry E, D’Souza D, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 2004, 179: 303-309. PMID: 15309376, DOI: 10.1007/s00213-004-1982-8.Peer-Reviewed Original ResearchConceptsGroup II metabotropic glutamate receptor agonistMetabotropic glutamate receptor agonistHealthy human subjectsNMDA glutamate receptor antagonistGlutamate receptor agonistsGlutamate receptor antagonistsTest dayCognitive effectsPerceptual changesKetamine infusionReceptor antagonistReceptor agonistDysphoric moodMemory impairmentBehavioral consequencesSignificant dose-related improvementGroup II mGluR agonistReceptor functionHuman subjectsMemoryNegative symptomsDose-related improvementNMDA receptor functionPreliminary evidenceDisruptive effects
2000
IV glycine and oral d-cycloserine effects on plasma and CSF amino acids in healthy humans
D’Souza D, Gil R, Cassello K, Morrissey K, Abi-Saab D, White J, Sturwold R, Bennett A, Karper L, Zuzarte E, Charney D, Krystal J. IV glycine and oral d-cycloserine effects on plasma and CSF amino acids in healthy humans. Biological Psychiatry 2000, 47: 450-462. PMID: 10704956, DOI: 10.1016/s0006-3223(99)00133-x.Peer-Reviewed Original ResearchMeSH KeywordsAcoustic StimulationAdministration, OralAdultAmino AcidsAntimetabolitesBiological AvailabilityCycloserineDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycineHumansInjections, IntravenousMaleMiddle AgedNeuropsychological TestsPsychiatric Status Rating ScalesReceptors, GlycineReceptors, N-Methyl-D-AspartateReflex, StartleSerineConceptsAcoustic startle responseN-methyl-D-aspartate (NMDA) glutamate receptorsD-cycloserineStartle responseCentral nervous system effectsTest dayCSF glycine levelsOral D-cycloserineCSF amino acidsNervous system effectsDouble-blind conditionsCognitive test performanceD-cycloserine effectsHealthy human subjectsCentral bioavailabilityIntravenous glycineLumbar punctureSecond test dayGlycine administrationModulates neurotransmissionGlycine levelsGlutamate receptorsCoagonist siteCerebrospinal fluidHealthy humans
1999
Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists
Krystal J, Belger A, D'Souza D, Anand A, Charney D, Aghajanian G, Moghaddam B. Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists. Neuropsychopharmacology 1999, 21: s143-s157. DOI: 10.1016/s0893-133x(99)00102-5.Peer-Reviewed Original ResearchHealthy human subjectsNMDA antagonist effectsNMDA antagonistsClinical studiesMetabotropic glutamate receptor agonistN-methyl-D-aspartate (NMDA) subtypeD2 receptor blockadeGlutamate receptor agonistsD2 receptor stimulationDopamine 2 receptorNovel pharmacologic strategiesEffects of ketaminePathophysiology of schizophreniaCourse of schizophreniaNovel pharmacotherapeutic strategiesHuman subjectsHyperglutamatergic stateSerotonin 2AGlutamate neuronsGlutamate releaseCerebral cortexPharmacologic strategiesCurrent antipsychoticsPharmacotherapeutic strategiesSubanesthetic dosesChanges of benzodiazepine receptors during chronic benzodiazepine administration in humans
Fujita M, Woods S, Verhoeff N, Abi-Dargham A, Baldwin R, Zoghbi S, Soares J, Jatlow P, Krystal J, Rajeevan N, Charney D, Seibyl J, Innis R. Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. European Journal Of Pharmacology 1999, 368: 161-172. PMID: 10193652, DOI: 10.1016/s0014-2999(99)00013-8.Peer-Reviewed Original ResearchConceptsClinical effectsReceptor levelsReceptor densityReceptor occupancyChronic benzodiazepine administrationBenzodiazepine receptor densityHealthy human subjectsComparison of baselineSingle photon emissionHopkins Verbal Learning TestInduced sedationVerbal Learning TestBenzodiazepine administrationOral administrationBaseline valuesBenzodiazepine receptorsTolerance developmentDay 3Day 17Day 4Day 10Central typeLearning TestReceptorsHuman subjects
1995
Effects of tryptophan depletion on responses to yohimbine in healthy human subjects
Goddard A, Charney D, Germine M, Woods S, Heninger G, Krystal J, Goodman W, Price L. Effects of tryptophan depletion on responses to yohimbine in healthy human subjects. Biological Psychiatry 1995, 38: 74-85. PMID: 7578653, DOI: 10.1016/0006-3223(94)00223-p.Peer-Reviewed Original ResearchConceptsHealthy human subjectsTryptophan depletionAlpha-2 adrenergic antagonist yohimbinePlacebo-controlled challenge testHuman subjectsAntagonist yohimbineNeurotransmitter systemsSerotonin systemChallenge testPossible functional interactionBiochemical variablesWhole groupFeelings of nervousnessNE functionMarked increaseNorepinephrineConsiderable evidenceFear responsesSubjectsHuman anxietyNervousnessCombination testControl testsFunctional interactionUnique changesNoradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine
McDougle C, Price L, Heninger G, Krystal J, Charney D. Noradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine. Psychopharmacology 1995, 118: 127-135. PMID: 7617798, DOI: 10.1007/bf02245830.Peer-Reviewed Original ResearchConceptsAcute ethanol administrationEthanol administrationPlasma MHPGIntravenous yohimbineBlood pressureNE turnoverSystolic blood pressureAlpha2-adrenergic receptorsPlacebo-controlled designBlood pressure measurementsEthanol-induced increaseHealthy human subjectsClear additive effectSubjective measuresNE metabolismNoradrenergic responsesNorepinephrine metaboliteCombined administrationMHPG responsePlasma levelsPharmacokinetic effectsOral administrationIntravenous administrationAnxiogenic effectsEthanol intoxication
1993
Yohimbine — facilitated acoustic startle reflex in humans
Morgan CA, Southwick SM, Grillon C, Davis M, Krystal JH, Charney DS. Yohimbine — facilitated acoustic startle reflex in humans. Psychopharmacology 1993, 110: 342-346. PMID: 7831429, DOI: 10.1007/bf02251291.Peer-Reviewed Original ResearchConceptsAcoustic startle reflexHealthy subjectsRandomized double-blind placebo-controlled designStartle amplitudeDouble-blind placebo-controlled designStartle reflexAlpha-2 receptor antagonistEffects of yohimbinePlacebo-controlled designDB intensityUseful animal modelHealthy human subjectsInstantaneous rise timeSaline placeboCardiovascular effectsExcitatory effectsNoradrenergic functionReceptor antagonistPlasma MHPGPreclinical studiesPeak anxietyYohimbineNeurochemical basisAnimal modelsRank testing
1992
Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine
Krystal J, McDougle C, Woods S, Price L, Heninger G, Charney D. Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine. Psychopharmacology 1992, 108: 313-319. PMID: 1355923, DOI: 10.1007/bf02245117.Peer-Reviewed Original ResearchConceptsHealthy subjectsDiastolic blood pressureΑ2-adrenergic receptorsSymptom scale scoresHealthy human subjectsDose-response relationshipIdazoxan doseBlood pressureOral yohimbineNorepinephrine metabolitePlasma levelsMedication effectsOral administrationPlasma MHPGPhysiologic indicesNeuroendocrine responsesΑ2 antagonistAdrenergic receptorsCortisol levelsScale scorePlasma cortisolYohimbineIdazoxanAnxiety statesReceptor specificity
1991
Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects
Seibyl J, Krystal J, Price L, Woods S, D'Amico C, Heninger G, Charney D. Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects. Psychiatry Research 1991, 38: 227-236. PMID: 1754635, DOI: 10.1016/0165-1781(91)90013-f.Peer-Reviewed Original ResearchConceptsGrowth hormone responseEffects of ritanserinHealthy male subjectsHealthy human subjectsSelf-rated anxietyMCPP infusionAgonist mCPPCardiovascular effectsHT2 receptorCardiovascular responsesNeuroendocrine responsesRitanserinHormone responseMale subjectsCortisol elevationBehavioral responsesHuman subjectsMCPPSubjectsResponsePlaceboPremedicationChlorophenylpiperazineInfusionAntagonist
1989
Effects of alprazolam and clonidine on carbon dioxide-induced increases in anxiety ratings in healthy human subjects
Woods S, Krystal J, Heninger G, Charney D. Effects of alprazolam and clonidine on carbon dioxide-induced increases in anxiety ratings in healthy human subjects. Life Sciences 1989, 45: 233-242. PMID: 2503670, DOI: 10.1016/0024-3205(89)90255-5.Peer-Reviewed Original ResearchConceptsHealthy human subjectsClonidine 2 mcg/Pulse rateEffects of alprazolamAnxiety-like effectsHuman subjectsRatings of anxietyOral alprazolamHypotensive effectVentilatory responseMcg/Noradrenergic systemBenzodiazepine receptorsAnxiolytic propertiesNeurobiologic mechanismsClonidineNew drugsAlprazolamAnxiety ratingsSubjective anxietyDrugsAnxietyNormal functioningNeural systemsUseful model system