2020
Medial PFC AMPA receptor and BDNF signaling are required for the rapid and sustained antidepressant-like effects of 5-HT1A receptor stimulation
Fukumoto K, Fogaça M, Liu RJ, Duman CH, Li XY, Chaki S, Duman RS. Medial PFC AMPA receptor and BDNF signaling are required for the rapid and sustained antidepressant-like effects of 5-HT1A receptor stimulation. Neuropsychopharmacology 2020, 45: 1725-1734. PMID: 32396921, PMCID: PMC7419563, DOI: 10.1038/s41386-020-0705-0.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorAntidepressant-like effectsMajor depressive disorderMedial prefrontal cortexMPFC infusionSelective stimulationReceptor antagonistAMPA receptorsNon-competitive N-methyl-D-aspartate (NMDA) receptor antagonistTreatment of MDDN-methyl-D-aspartate receptor antagonistSynaptic functionAntidepressant-like actionNovelty-suppressed feedingAMPA receptor antagonistGlutamate AMPA receptorsMPFC 5Antidepressant effectsNeurotrophic factorReceptor agonistDepressive disorderSerotonergic systemReceptor stimulationReceptor activationSynaptic proteinsGABA 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 disorders
2019
Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents
Ghosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, Wohleb E, Fogaca MV, Teichman EM, Hare B, Duman RS. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents. Neurobiology Of Disease 2019, 134: 104669. PMID: 31707118, DOI: 10.1016/j.nbd.2019.104669.Peer-Reviewed Original ResearchConceptsChronic unpredictable stressMedial prefrontal cortexInhibitory post-synaptic currentsGABAergic transmissionSingle doseMale rodentsPrefrontal cortexImbalance of inhibitoryMPFC pyramidal neuronsDepressive-like behaviorDepression-like behaviorStress-induced impairmentModel of depressionPost-synaptic currentsPrecise cellular mechanismsGABAergic proteinsAntidepressant ketamineSynaptic deficitsGABAergic synapsesPyramidal neuronsSynaptic markersGABA markersGlutamate neurotransmissionDepressive behaviorGABA neurotransmissionN-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 culturesSestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
Kato T, Pothula S, Liu RJ, Duman CH, Terwilliger R, Vlasuk GP, Saiah E, Hahm S, Duman RS. Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation. Journal Of Clinical Investigation 2019, 129: 2542-2554. PMID: 30990795, PMCID: PMC6546461, DOI: 10.1172/jci126859.Peer-Reviewed Original ResearchConceptsMedial prefrontal cortexRapid acting antidepressantsActing antidepressantsAntidepressant actionAntidepressant effectsBDNF releaseActivity-dependent BDNF releaseRapid antidepressant effectsBlood-brain barrierChronic stress exposureSynaptic deficitsBDNF polymorphismSingle doseBrain barrierSynapse numberPreclinical studiesPharmacological modulationNeuronal activityChronic stressPrefrontal cortexRapid synapticStress exposureBehavioral responsesAmino acid leucineAntidepressants
2018
Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine
Fukumoto K, Fogaça M, Liu RJ, Duman C, Kato T, Li XY, Duman RS. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 116: 297-302. PMID: 30559184, PMCID: PMC6320534, DOI: 10.1073/pnas.1814709116.Peer-Reviewed Original ResearchConceptsActivity-dependent BDNF releaseAntidepressant effectsAntidepressant actionBDNF releaseActivity-dependent brain-derived neurotrophic factorL-type voltage-dependent CaSynaptic functionBrain-derived neurotrophic factorMajor depressive disorder patientsMethyl-d-aspartate (NMDA) receptor antagonistIntra-mPFC microinjectionRapid antidepressant effectsDepressive disorder patientsTreatment of MDDBDNF Val66Met allelesVoltage-dependent CaIntra-mPFC infusionMetabolite of ketamineDownstream TrkBNeurotrophic factorReceptor antagonistNMDA receptorsMolecular signaling mechanismsRodent modelsDisorder patients
2017
Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior
Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior. Biological Psychiatry 2017, 83: 38-49. PMID: 28697890, PMCID: PMC6506225, DOI: 10.1016/j.biopsych.2017.05.026.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnxietyChronic DiseaseDepressive DisorderDisease Models, AnimalFemaleMacrophage Colony-Stimulating FactorMaleMice, Inbred C57BLMice, TransgenicMicrogliaNeuronal PlasticityNeuronsPhagocytosisPrefrontal CortexReceptor, Macrophage Colony-Stimulating FactorRNA, MessengerSex CharacteristicsStress, PsychologicalUncertaintyConceptsDepressive-like behaviorChronic unpredictable stressMedial prefrontal cortexDendritic spine densityNeuronal remodelingSynaptic deficitsDevelopment of anxietyMessenger RNA levelsPrefrontal cortexSpine densityFemale miceFunctional changesStress exposureNeuron-microglia interactionsRNA levelsChronic stress exposureStress-induced elevationPostmortem dorsolateral prefrontal cortexDorsolateral prefrontal cortexBehavioral consequencesNeuronal atrophyPyramidal neuronsMicroglia functionMale miceUnpredictable stress
2016
GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine
Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, Burgdorf J, Moskal J, Taylor J, Aghajanian G, Duman RS. GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine. Neuropsychopharmacology 2016, 42: 1231-1242. PMID: 27634355, PMCID: PMC5437877, DOI: 10.1038/npp.2016.202.Peer-Reviewed Original ResearchConceptsPsychotomimetic side effectsGLYX-13Prefrontal cortexSide effectsGlycine-site partial agonist propertiesLayer V pyramidal neuronsSerial reaction time taskAntidepressant behavioral actionsBehavioral actionsRapid antidepressant effectsRapid acting antidepressantsRapid antidepressant responseApical dendritic tuftsMedial PFCNMDA receptor modulatorsPartial agonist propertiesMedial prefrontal cortexActing antidepressantsAntidepressant actionAntidepressant effectsThalamocortical synapsesAntidepressant responsePyramidal neuronsSingle doseDendritic tufts
2015
Spine synapse remodeling in the pathophysiology and treatment of depression
Duman CH, Duman RS. Spine synapse remodeling in the pathophysiology and treatment of depression. Neuroscience Letters 2015, 601: 20-29. PMID: 25582786, PMCID: PMC4497940, DOI: 10.1016/j.neulet.2015.01.022.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsSynaptic protein synthesisPrefrontal cortexSpine densityTreatment-resistant MDD patientsChronic antidepressant treatmentSpine synapse numberControl of moodChronic stress modelSynapse connectivityTreatment of depressionLimbic brain regionsPFC of rodentsRapid therapeutic actionDendrite complexityRegion-specific effectsSynaptogenic hypothesisAntidepressant treatmentAntidepressant ketamineBDNF regulationNeurotrophic factorMDD patientsDepressed patientsSynapse alterationsSynapse numberFunctional abnormalities
2014
REDD1 is essential for stress-induced synaptic loss and depressive behavior
Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, Dutheil S, Duman C, Boikess S, Lewis DA, Stockmeier CA, DiLeone RJ, Rex C, Aghajanian GK, Duman RS. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nature Medicine 2014, 20: 531-535. PMID: 24728411, PMCID: PMC4016190, DOI: 10.1038/nm.3513.Peer-Reviewed Original Research
2013
Evaluating Effects of EPO in Rodent Behavioral Assays Related to Depression
Duman C, Newton S. Evaluating Effects of EPO in Rodent Behavioral Assays Related to Depression. Methods In Molecular Biology 2013, 982: 127-140. PMID: 23456866, DOI: 10.1007/978-1-62703-308-4_8.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsForced-swim testNeurotrophic actionsNovel object recognition testPotential antidepressant propertiesTreatment of depressionTissue-protective propertiesObject recognition testPotential therapeutic utilityEffect of erythropoietinRodent behavioral modelsAntidepressant propertiesDepressive disorderRodent modelsTherapeutic utilityRodent behavioral assaysNeurotrophic compoundsHyponeophagia testErythropoietinCytokine erythropoietinDepressionImportant regulatorBehavioral assaysProtective propertiesRecognition testAntidepressants
2010
Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats
Hermes G, Li N, Duman C, Duman R. Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats. Physiology & Behavior 2010, 104: 354-359. PMID: 21185848, PMCID: PMC3387788, DOI: 10.1016/j.physbeh.2010.12.019.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsAnimals, NewbornBehavioral SymptomsBody WeightDisks Large Homolog 4 ProteinEstriolEstrusExploratory BehaviorFemaleFood DeprivationGene Expression Regulation, DevelopmentalIntracellular Signaling Peptides and ProteinsMembrane ProteinsPrefrontal CortexPregnancyRatsRats, Sprague-DawleyReceptors, AMPAReceptors, N-Methyl-D-AspartateSocial IsolationSynapsinsConceptsFemale ratsNovelty-suppressed feeding testPrefrontal cortexSocial isolationPost-weaning social isolationSynapse-related proteinsChronic social isolationFemale Sprague-DawleyEarly life stressorsSerotonergic functionGlutamate receptorsSprague-DawleyMale rodentsMaternal separationProtein PSD95Profound dysregulationNeuropsychiatric disordersBrain developmentRatsAnxiety disordersMarked deficitDeprivation resultsProtein expressionAdult animalsBiochemical effectsChapter One Models of Depression
Duman C. Chapter One Models of Depression. Vitamins & Hormones 2010, 82: 1-21. PMID: 20472130, DOI: 10.1016/s0083-6729(10)82001-1.ChaptersConceptsChronic mild stress modelEarly-life stress modelStress exposureAvailable drug treatmentsDepressive-like stateTail suspension testAntidepressant drug responseSignificant health burdenDepressive illnessSwim testHealth burdenDrug treatmentQuantifiable correlatesSuspension testShort-term exposureDisease processAnimal modelsExperimental animalsDepression attemptUncontrollable stressHuman symptomsDrug responseDepressionExposurePredictive validity
2009
Erythropoietin Induction by Electroconvulsive Seizure, Gene Regulation, and Antidepressant-Like Behavioral Effects
Girgenti MJ, Hunsberger J, Duman CH, Sathyanesan M, Terwilliger R, Newton SS. Erythropoietin Induction by Electroconvulsive Seizure, Gene Regulation, and Antidepressant-Like Behavioral Effects. Biological Psychiatry 2009, 66: 267-274. PMID: 19185286, DOI: 10.1016/j.biopsych.2008.12.005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntidepressive AgentsBehavior, AnimalBrain-Derived Neurotrophic FactorDepressionDisease Models, AnimalElectroshockErythropoietinExploratory BehaviorGene Expression ProfilingGene Expression RegulationHumansHypoxia-Inducible Factor 1, alpha SubunitLocomotionMaleOligonucleotide Array Sequence AnalysisRatsRats, Sprague-DawleyReceptors, ErythropoietinSeizuresSwimmingConceptsElectroconvulsive seizuresBehavioral effectsNIH testEPO receptorTrophic effectsRobust antidepressant-like effectsAntidepressant-like behavioral effectsBrain-derived neurotrophic factorAntidepressant-like efficacyTranscription factor hypoxiaAntidepressant-like effectsMultiple brain regionsQuantitative polymerase chain reactionExpression of erythropoietinAntidepressant actionAntidepressant effectsPeripheral administrationNeurotrophic factorIntracerebroventricular infusionPolymerase chain reactionTrophic actionNeurotrophic genesAnimal modelsChoroid plexusRegulation of erythropoietin
2008
Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise
Duman CH, Schlesinger L, Terwilliger R, Russell DS, Newton SS, Duman RS. Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise. Behavioural Brain Research 2008, 198: 366-371. PMID: 19056428, PMCID: PMC2729431, DOI: 10.1016/j.bbr.2008.11.016.Peer-Reviewed Original ResearchConceptsInsulin-like growth factorAntidepressant-like behaviorForced-swim testGrowth factorChronic IGF-I treatmentNovelty-induced hypophagia testIGF-I administrationEffects of exerciseIGF-I treatmentAntidepressant effectsHypophagia testNeurotrophic factorNeurotrophic mechanismsStress exposureDepressionFunctional relevanceTreatmentFactorsMiceAdministrationBrainCorrigendum to “Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice” [Brain Res. 1199 (2008) 148–158]
Duman C, Schlesinger L, Russell D, Duman R. Corrigendum to “Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice” [Brain Res. 1199 (2008) 148–158]. Brain Research 2008, 1218: 313. DOI: 10.1016/j.brainres.2008.04.053.Peer-Reviewed Original ResearchVoluntary exercise produces antidepressant and anxiolytic behavioral effects in mice
Duman CH, Schlesinger L, Russell DS, Duman RS. Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice. Brain Research 2008, 1199: 148-158. PMID: 18267317, PMCID: PMC2330082, DOI: 10.1016/j.brainres.2007.12.047.Peer-Reviewed Original ResearchMeSH KeywordsAmitriptylineAnalysis of VarianceAnimalsAntidepressive Agents, TricyclicAnxietyBehavior, AnimalBrain-Derived Neurotrophic FactorDepressionDisease Models, AnimalEscape ReactionHelplessness, LearnedMaleMaze LearningMiceMice, Inbred C57BLMice, KnockoutMotor ActivityPain MeasurementPhysical Conditioning, AnimalReaction TimeSwimmingTime FactorsConceptsBrain-derived neurotrophic factorAntidepressant-like behavioral responsesAntidepressant-like behavioral changesHeterozygous BDNF knockout miceBDNF knockout miceAntidepressant drug treatmentAntidepressant-like behaviorWheel-running exerciseDrug-treated animalsWild-type miceAnxiolytic behavioral effectsFST performanceSedentary control miceBDNF mRNASubchronic administrationChronic exerciseControl miceNeurotrophic factorBasic research studiesBehavioral responsesVoluntary exerciseBDNF geneDrug treatmentKnockout miceLocomotor activity
2007
Antidepressant actions of the exercise-regulated gene VGF
Hunsberger JG, Newton SS, Bennett AH, Duman CH, Russell DS, Salton SR, Duman RS. Antidepressant actions of the exercise-regulated gene VGF. Nature Medicine 2007, 13: 1476-1482. PMID: 18059283, DOI: 10.1038/nm1669.Peer-Reviewed Original ResearchConceptsAntidepressant actionAntidepressant responseRobust antidepressant responseAction of antidepressantsAntidepressant drug developmentVGF nerve growth factorVGF-derived peptidesPotential therapeutic targetDepressed human subjectsNerve growth factorGrowth factor pathwaysNeurotrophic factorMouse hippocampusTherapeutic targetSynaptic plasticityBrain regionsFactor pathwayGrowth factorTarget genesCustom microarrayHealth benefitsPathway analysisVGFHuman subjectsDrug development
2006
A Role for MAP Kinase Signaling in Behavioral Models of Depression and Antidepressant Treatment
Duman CH, Schlesinger L, Kodama M, Russell DS, Duman RS. A Role for MAP Kinase Signaling in Behavioral Models of Depression and Antidepressant Treatment. Biological Psychiatry 2006, 61: 661-670. PMID: 16945347, DOI: 10.1016/j.biopsych.2006.05.047.Peer-Reviewed Original ResearchMeSH KeywordsAnalysis of VarianceAniline CompoundsAnimalsAntidepressive AgentsBehavior, AnimalBenzamidesBrain-Derived Neurotrophic FactorDepressionDisease Models, AnimalDose-Response Relationship, DrugDrug InteractionsEnzyme InhibitorsHelplessness, LearnedHindlimb SuspensionMaleMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase KinasesMotor ActivitySignal TransductionSwimmingConceptsBrain-derived neurotrophic factorAntidepressant-like effectsAntidepressant treatmentSwim testBDNF heterozygous knockout miceDepressive-like behaviorDepressive-like phenotypeTail suspension testEffects of desipramineHeterozygous knockout miceDepressive behavioral phenotypeEffect of inhibitionRodent behavioral modelsMouse behavioral modelsHeterozygous gene deletionAntidepressant mechanismAcute administrationAcute blockadeNeurotrophic factorAntidepressant drugsSuspension testDepressive phenotypeKnockout miceMEK inhibitionMEK inhibitorsTNFα Signaling in Depression and Anxiety: Behavioral Consequences of Individual Receptor Targeting
Simen BB, Duman CH, Simen AA, Duman RS. TNFα Signaling in Depression and Anxiety: Behavioral Consequences of Individual Receptor Targeting. Biological Psychiatry 2006, 59: 775-785. PMID: 16458261, DOI: 10.1016/j.biopsych.2005.10.013.Peer-Reviewed Original ResearchMeSH KeywordsAnalysis of VarianceAnimalsAnxietyBehavior, AnimalConditioning, PsychologicalDepressionDisease Models, AnimalDrinking BehaviorExploratory BehaviorFearGene ExpressionMaze LearningMiceMice, Inbred C57BLMice, KnockoutMotor ActivityReaction TimeReceptors, Tumor Necrosis FactorReceptors, Tumor Necrosis Factor, Type IReceptors, Tumor Necrosis Factor, Type IIReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSignal TransductionSucroseSwimmingTumor Necrosis Factor Decoy ReceptorsTumor Necrosis Factor-alphaConceptsPro-inflammatory cytokinesAntidepressant-like responseDepression-like behaviorDepression-like symptomsDeletion of TNFR1Acute injectionSerum levelsSwim testDepressed patientsMajor depressionReceptor subtypesSickness behaviorWildtype littermatesDepressive symptomsDrinking testPsychiatric conditionsCytokinesReceptor targetingSymptomsFear conditioningPatientsTNFalphaExploratory behaviorMiceBehavioral consequences