2024
Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses
Fogaça M, Daher F, Picciotto M. Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses. Neuropsychopharmacology 2024, 1-12. PMID: 39390105, DOI: 10.1038/s41386-024-02002-1.Peer-Reviewed Original ResearchNovelty suppressed feeding testMedial prefrontal cortexSucrose splash testEffects of ketamineAntidepressant-like responseMajor depressive disorderGABAergic activityGABA interneuronsGlutamatergic activityGABA neuronsSustained antidepressant effectsGABA neuron activityLow dose of ketamineAdministration of ketamineDose of ketamineAntidepressant responseAntidepressant developmentSplash testAntidepressant effectsPrefrontal cortexDepressive disorderChemogenetic inhibitionBehavioral actionsAssociated with disruptionGABA functionMedial prefrontal cortex acetylcholine signaling mediates the ability to learn an active avoidance response following learned helplessness training
Abdulla Z, Mineur Y, Crouse R, Etherington I, Yousuf H, Na J, Picciotto M. Medial prefrontal cortex acetylcholine signaling mediates the ability to learn an active avoidance response following learned helplessness training. Neuropsychopharmacology 2024, 1-9. PMID: 39362985, DOI: 10.1038/s41386-024-02003-0.Peer-Reviewed Original ResearchMedial prefrontal cortexACh levelsInescapable stressorEscape performanceExposure to inescapable stressorsAcetylcholine signalingLearned helplessness taskLearned helplessness trainingStress-related circuitsActive avoidance taskActive avoidance testActive avoidance responseElevation of acetylcholineIncreased ACh levelsStress-related behaviorsImpaired escape performanceIncreased brain levelsTop-down controlHelplessness trainingPrefrontal cortexAvoidance taskChemogenetic inhibitionMaladaptive behaviorsAvoidance testNegative encoding
2022
Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear
Lee B, Pothula S, Wu M, Kang H, Girgenti MJ, Picciotto MR, DiLeone RJ, Taylor JR, Duman RS. Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear. Molecular Psychiatry 2022, 27: 2580-2589. PMID: 35418600, PMCID: PMC9135632, DOI: 10.1038/s41380-022-01498-7.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderFear extinctionInfralimbic medial prefrontal cortexFear conditioning modelEnhanced fear extinctionFear-based behaviorsProlonged stress modelMedial prefrontal cortexSpontaneous recoveryIL-mPFCPTSD modelPTSD treatmentStress disorderPrefrontal cortexSPS modelN-methyl-D-aspartate receptor modulatorsBrain-derived neurotrophic factorN-methyl-D-aspartate receptorsBehavioral effectsIncreased attentionMPFCPreclinical findingsPyramidal neuronsNeurotrophic factorMale mice
2020
Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons
Pothula S, Liu RJ, Wu M, Sliby AN, Picciotto MR, Banerjee P, Duman RS. Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons. Neuropsychopharmacology 2020, 46: 799-808. PMID: 33059355, PMCID: PMC8027594, DOI: 10.1038/s41386-020-00882-7.Peer-Reviewed Original ResearchConceptsAntidepressant-like effectsMedial prefrontal cortexRapid antidepressant-like effectsGluN2B-containing NMDARsPositive allosteric modulatorsNMDAR positive allosteric modulatorExcitatory neuronsExerts antidepressant-like effectsAntidepressant-like behavioral effectsPrefrontal cortexBehavioral effectsAkt/mTORAntidepressant-like actionChronic unpredictable stressNMDA receptor activityRecent preclinical studiesMajor depressive disorderSpecific knockdownParvalbumin inhibitory neuronsCellular triggersSynaptic proteinsGlutamatergic systemNMDAR activityClinical trialsDepressive disorderCumulative Effects of Social Stress on Reward-Guided Actions and Prefrontal Cortical Activity
Barthas F, Hu MY, Siniscalchi MJ, Ali F, Mineur YS, Picciotto MR, Kwan AC. Cumulative Effects of Social Stress on Reward-Guided Actions and Prefrontal Cortical Activity. Biological Psychiatry 2020, 88: 541-553. PMID: 32276717, PMCID: PMC7434704, DOI: 10.1016/j.biopsych.2020.02.008.Peer-Reviewed Original ResearchConceptsPrefrontal cortical activityCortical activityIndividual layer 2/3 pyramidal neuronsLayer 2/3 pyramidal neuronsStress exposureDepressive-like phenotypeTwo-photon calcium imagingSocial stressChronic social stressIndividual prefrontal neuronsMedial prefrontal cortexPyramidal neuronsMotor subregionsNeural dysfunctionResilient miceCalcium imagingPrefrontal neuronsAbnormal levelsPrefrontal cortexSocial defeatDistinct neural responsesStress-induced lossGoal-directed actionsEnsemble activityDefeat sessionsGABA 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
Sex differences in amphetamine-induced dopamine release in the dorsolateral prefrontal cortex of tobacco smokers
Zakiniaeiz Y, Hillmer AT, Matuskey D, Nabulsi N, Ropchan J, Mazure CM, Picciotto MR, Huang Y, McKee SA, Morris ED, Cosgrove KP. Sex differences in amphetamine-induced dopamine release in the dorsolateral prefrontal cortex of tobacco smokers. Neuropsychopharmacology 2019, 44: 2205-2211. PMID: 31269510, PMCID: PMC6897943, DOI: 10.1038/s41386-019-0456-y.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsDA releasePositron emission tomographyD2R availabilityDorsolateral prefrontal cortexMale smokersFemale smokersTobacco smokingPrefrontal cortexAmphetamine-induced DA releaseAmphetamine-induced dopamine releaseCortical DA releaseMesocortical DA systemEffects of nicotineSmoking-related behaviorsMesolimbic dopamine systemLong-term abstinenceSex differencesGender-specific treatmentFemale nonsmokersTobacco smokersAmphetamine administrationDopamine releaseNeurochemical mechanismsNonsmokersSmokersRole of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine
Deyama S, Bang E, Wohleb ES, Li XY, Kato T, Gerhard DM, Dutheil S, Dwyer JM, Taylor SR, Picciotto MR, Duman RS. Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine. American Journal Of Psychiatry 2019, 176: 388-400. PMID: 30606046, PMCID: PMC6494682, DOI: 10.1176/appi.ajp.2018.17121368.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingBehavior, AnimalExcitatory Amino Acid AntagonistsGene Knockdown TechniquesGene Knockout TechniquesIn Vitro TechniquesKetamineMiceNeuronsPrefrontal CortexQuinazolinesSignal TransductionVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsNeuronal vascular endothelial growth factorVascular endothelial growth factorMedial prefrontal cortexRapid antidepressant actionsAntidepressant actionIntra-mPFC infusionSystemic ketamineBehavioral actionsFlk-1Conventional monoamine-based antidepressantsPrefrontal cortexRole of VEGFRapid antidepressant effectsTreatment-resistant depressionMethyl-d-aspartate receptor antagonist ketamineNeuron-specific deletionMonoamine-based antidepressantsNeuron-specific knockoutViral-mediated knockdownEndothelial growth factorVEGF-Flk-1Synaptogenic actionsAntidepressant effectsSynaptogenic effectsLocal knockdown
2015
Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice
Mineur YS, Bentham MP, Zhou WL, Plantenga ME, McKee SA, Picciotto MR. Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice. Psychopharmacology 2015, 232: 3539-3549. PMID: 26146014, PMCID: PMC4561580, DOI: 10.1007/s00213-015-4001-3.Peer-Reviewed Original ResearchConceptsAntidepressant-like effectsPaired-pulse ratioC-Fos immunoreactivityPrefrontal cortexSwim testBrain areasRobust antidepressant-like effectsBrain regionsSex differencesMale C57BL/6J miceDepression-like behaviorEffects of guanfacineAcetylcholinesterase inhibitor physostigmineLight/dark boxBaseline sex differencesC-fos expressionDepression-like stateCritical brain regionsDifferent brain areasSex-specific changesAntidepressant efficacyCholinergic controlInhibitor physostigmineC57BL/6J miceAgonist guanfacine
2013
Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex
Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 12078-12083. PMID: 23818597, PMCID: PMC3718126, DOI: 10.1073/pnas.1307849110.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcholineAconitineAlpha7 Nicotinic Acetylcholine ReceptorAnalysis of VarianceAnimalsBridged Bicyclo Compounds, HeterocyclicCholinergic AgonistsCholinergic AntagonistsCognitionFemaleIontophoresisMacaca mulattaMaleMecamylamineMicroscopy, ImmunoelectronN-MethylaspartatePhenolsPiperidinesPrefrontal CortexQuinuclidinesReceptors, NicotinicSpatial BehaviorSynapsesVisual PerceptionConceptsDorsolateral prefrontal cortexΑ7 nAChRsPrefrontal cortexΑ7 nicotinic acetylcholine receptorGlutamatergic NMDA receptorsCognitive circuitsNicotinic α7 receptorsPrimary visual cortexNMDA receptor actionGenetic insultsNicotinic acetylcholine receptorsDlPFC circuitsPrimate dlPFCACh depletionNMDA actionNMDA receptorsPyramidal cellsΑ7 receptorsNeuronal firingNAChR blockadeAcetylcholine receptorsVisual cortexPersistent firingCognitive functionLow-dose stimulation
2011
Plasticity of Prefrontal Attention Circuitry: Upregulated Muscarinic Excitability in Response to Decreased Nicotinic Signaling Following Deletion of α5 or β2 Subunits
Tian MK, Bailey CD, De Biasi M, Picciotto MR, Lambe EK. Plasticity of Prefrontal Attention Circuitry: Upregulated Muscarinic Excitability in Response to Decreased Nicotinic Signaling Following Deletion of α5 or β2 Subunits. Journal Of Neuroscience 2011, 31: 16458-16463. PMID: 22072695, PMCID: PMC3240894, DOI: 10.1523/jneurosci.3600-11.2011.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcholineAconitineAge FactorsAnalysis of VarianceAnimalsAtropineDihydro-beta-ErythroidineIntracellular Signaling Peptides and ProteinsMaleMembrane PotentialsMiceMice, KnockoutNeuronal PlasticityNeuronsNeuropeptidesNeurotransmitter AgentsNicotineNicotinic AntagonistsOrexinsPatch-Clamp TechniquesPrefrontal CortexReceptors, MuscarinicReceptors, NicotinicSignal TransductionUp-RegulationConceptsLayer VI neuronsNicotinic receptorsCholinergic excitationCholinergic receptorsPrefrontal cortexExcitatory muscarinic receptorsPrefrontal attention circuitryMuscarinic cholinergic receptorsMuscarinic acetylcholine receptorsAcute brain slicesWild-type miceWhole-cell recordingsΒ2 subunitNicotinic receptor subunitsMedial prefrontal cortexPyramidal neuronsMuscarinic receptorsNicotinic signalingLayer VIAttention circuitryCholinergic stimulationBrain slicesNicotinic stimulationAcetylcholine receptorsTiming of excitation
2003
In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice
Brunzell DH, Russell DS, Picciotto MR. In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. Journal Of Neurochemistry 2003, 84: 1431-1441. PMID: 12614343, DOI: 10.1046/j.1471-4159.2003.01640.x.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAmygdalaAnimalsCotinineCyclic AMP Response Element-Binding ProteinDrug Administration ScheduleLimbic SystemMaleMesencephalonMiceMice, Inbred C57BLMitogen-Activated Protein KinasesNicotineNicotinic AgonistsNucleus AccumbensPhosphorylationPrefrontal CortexSignal TransductionTobacco Use DisorderVentral Tegmental AreaConceptsCAMP response element-binding proteinChronic nicotine exposureChronic nicotineNicotine exposurePrefrontal cortexC57BL/6J miceTyrosine hydroxylaseNicotine dependenceCREB phosphorylationVentral tegmental areaCREB activityResponse element-binding proteinCatecholaminergic toneNicotine treatmentNicotine withdrawalNicotine reinforcementTegmental areaNucleus accumbensNeuronal plasticityElement-binding proteinDrug reinforcementChronic exposureTH levelsNeural plasticityWestern blottingNicotine Induces Glutamate Release from Thalamocortical Terminals in Prefrontal Cortex
Lambe EK, Picciotto MR, Aghajanian GK. Nicotine Induces Glutamate Release from Thalamocortical Terminals in Prefrontal Cortex. Neuropsychopharmacology 2003, 28: 216-225. PMID: 12589374, DOI: 10.1038/sj.npp.1300032.Peer-Reviewed Original ResearchConceptsPrefrontal cortexSpontaneous excitatory postsynaptic currentsPrefrontal cortical activationEmotional cuesHigh-affinity nicotinic receptorsCognitive functionCortical activationThalamocortical terminalsGlutamate releaseBrain regionsLayer V pyramidal neuronsCognitionPrefrontal cortical slicesExcitatory postsynaptic currentsRelease of glutamateCortexStimulation of nAChRsNicotinic acetylcholine receptorsΑ4β2 nAChRsDifferent neurotransmittersCerebral cortexPyramidal neuronsCortical slicesPostsynaptic currentsΜ-opioid
2001
Effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in rats: dissociation of biochemical and behavioral effects
George T, Picciotto M, Verrico C, Roth R. Effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in rats: dissociation of biochemical and behavioral effects. Biological Psychiatry 2001, 49: 300-306. PMID: 11230881, DOI: 10.1016/s0006-3223(00)00928-8.Peer-Reviewed Original ResearchConceptsConditioned fear stressNicotine pretreatmentMedial prefrontal cortexFear stressDopamine metabolismNucleus accumbensPrefrontal cortexAcute footshock stressImmobility responseBehavioral responsesCortical dopaminergicDopamine utilizationCortical dopamineNicotine exposureFootshock stressNicotine dependenceAnxiolytic activityConditioned fear paradigmNicotine differsDay 21Psychological stressorsBehavioral effectsDopaminergicClinical contextPreferential activation