2020
Muscarinic M1 Receptors Modulate Working Memory Performance and Activity via KCNQ Potassium Channels in the Primate Prefrontal Cortex
Galvin VC, Yang ST, Paspalas CD, Yang Y, Jin LE, Datta D, Morozov YM, Lightbourne TC, Lowet AS, Rakic P, Arnsten AFT, Wang M. Muscarinic M1 Receptors Modulate Working Memory Performance and Activity via KCNQ Potassium Channels in the Primate Prefrontal Cortex. Neuron 2020, 106: 649-661.e4. PMID: 32197063, PMCID: PMC7244366, DOI: 10.1016/j.neuron.2020.02.030.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFemaleKCNQ Potassium ChannelsMacaca mulattaMaleMemory, Short-TermNeuronsPrefrontal CortexReceptor, Muscarinic M1ConceptsKCNQ channelsInverted-U dose responseCell firingPrefrontal cortexMuscarinic M1 receptorsKCNQ potassium channelsSingle-unit recordingsPrimate prefrontal cortexDorsolateral prefrontal cortexCholinergic alterationsKCNQ isoformsM1 receptorsPyramidal neuronsCholinergic depletionMuscarinic M1Cognitive disordersAged monkeysPersistent firingRecurrent excitationPotassium channelsAppropriate targetsDose responseM1R stimulationSensory inputCortex
2019
Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex
Datta D, Yang ST, Galvin VC, Solder J, Luo F, Morozov YM, Arellano J, Duque A, Rakic P, Arnsten A, Wang M. Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex. Journal Of Neuroscience 2019, 39: 2722-2734. PMID: 30755491, PMCID: PMC6445993, DOI: 10.1523/jneurosci.2472-18.2019.Peer-Reviewed Original ResearchConceptsΑ1-AR stimulationPosttraumatic stress disorderExcitatory effectsNeuronal firingDorsolateral prefrontal cortexBasal conditionsPrefrontal cortexΑ1-ARΑ1-adrenoceptorsInverted-U dose responseUncontrollable stressStress disorderTreatment of PTSDPrimate dorsolateral prefrontal cortexΑ1-AR expressionMajority of neuronsΑ1-AR agonistsPrefrontal cortical physiologyNoradrenergic releasePresynaptic excitationEndogenous NEPostsynaptic actionsExcitatory actionGlutamate releaseAxon terminals
2017
The aged rhesus macaque manifests Braak stage III/IV Alzheimer's‐like pathology
Paspalas CD, Carlyle BC, Leslie S, Preuss TM, Crimins JL, Huttner AJ, van Dyck C, Rosene DL, Nairn AC, Arnsten AFT. The aged rhesus macaque manifests Braak stage III/IV Alzheimer's‐like pathology. Alzheimer's & Dementia 2017, 14: 680-691. PMID: 29241829, PMCID: PMC6178089, DOI: 10.1016/j.jalz.2017.11.005.Peer-Reviewed Original ResearchConceptsLate-onset Alzheimer's diseaseCortical pathologyEntorhinal cortexAnimal modelsBraak stage III/IVAlzheimer's diseaseStage III/IVRhesus macaquesProgression of tauAlzheimer-like pathologyPrimary visual cortexSequence of tauDorsolateral prefrontal cortexTau pathologyPreventive strategiesAssociation cortexVisual cortexPrefrontal cortexCortexPathologyDiseaseOld animalsProtein kinase A (PKA) phosphorylationGenetic insultsMacaquesmGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks
Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AF, Paspalas CD. mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks. Cerebral Cortex 2017, 28: 974-987. PMID: 28108498, PMCID: PMC5974790, DOI: 10.1093/cercor/bhx005.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsDose-Response Relationship, DrugExcitatory Amino Acid AgentsEye MovementsFemaleImage Processing, Computer-AssistedMacaca mulattaMagnetic Resonance ImagingMaleMemory, Short-TermNeuronsPost-Synaptic DensityPrefrontal CortexRatsReceptors, Metabotropic GlutamateSpatial LearningSubcellular FractionsConceptsPrimate dorsolateral prefrontal cortexMetabotropic glutamate receptorsDorsolateral prefrontal cortexGlutamate receptorsCell firingPrefrontal cortexMGluR2 positive allosteric modulatorsFocus of pathologyNovel therapeutic targetPositive allosteric modulatorsMGluR3 agonistGlutamate transmissionAstrocytic expressionGlial receptorsPostsynaptic componentsSpine synapsesInhibition of cAMPN-acetylaspartylglutamateMGluR3Therapeutic targetCognitive disordersLayer IIIMGluR2Postsynaptic cAMPAlzheimer's disease
2014
cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex
Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE, Simen AA, Ramos BP, Bordner KA, Craft GE, Davies P, Pletikos M, Šestan N, Arnsten AF, Paspalas CD. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 5036-5041. PMID: 24707050, PMCID: PMC3977284, DOI: 10.1073/pnas.1322360111.Peer-Reviewed Original ResearchConceptsNeurofibrillary tanglesAssociation cortexAlzheimer's diseaseSpine apparatusPhosphorylated tauPattern of neurodegenerationLate-stage diseaseHigh-risk factorsNormal aged miceGenetic rodent modelsPrefrontal association cortexPrimary sensory cortexPrimary visual cortexAge-related increasePyramidal neuronsCorticocortical connectionsAged miceRisk factorsGlutamate synapsesSpine synapsesSelective vulnerabilityRodent modelsDendritic spinesSensory cortexProtein kinase phosphorylation
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 stimulationNMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex
Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF. NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex. Neuron 2013, 77: 736-749. PMID: 23439125, PMCID: PMC3584418, DOI: 10.1016/j.neuron.2012.12.032.Peer-Reviewed Original ResearchConceptsPersistent firingDorsolateral prefrontal cortexAMPA receptorsPrefrontal cortexPrimate dorsolateral prefrontal cortexSystemic ketamine administrationPersistent neuronal firingAMPAR blockadePrimate dlPFCKetamine actionKetamine administrationNMDAR blockadeNMDA receptorsSystemic ketamineNetwork firingNeuronal firingAlzheimer's diseaseReceptor influencesImpair cognitionResponse cellsRecurrent excitationSensory stimulation
2007
α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex
Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF. α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex. Cell 2007, 129: 397-410. PMID: 17448997, DOI: 10.1016/j.cell.2007.03.015.Peer-Reviewed Original ResearchConceptsHCN channel blockadePrefrontal cortical neuronsDelay-related firingΑ2A adrenoceptorsChannel blockadeCortical neuronsInhibition of cAMPAlpha2A adrenoceptorsDendritic spinesNetwork firingElectrophysiological studiesPFC neuronsRecurrent excitationFunctional connectivityHCN channelsPrefrontal cortexHCN1 channelsPFC networksCAMP inhibitionStimulationBlockadeInverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nature Neuroscience 2007, 10: 376-384. PMID: 17277774, DOI: 10.1038/nn1846.Peer-Reviewed Original ResearchAction PotentialsAnalysis of VarianceAnimalsBehavior, AnimalCyclic AMPDopamine AgentsDose-Response Relationship, DrugDrug InteractionsIontophoresisMacaca mulattaMaleMaze LearningMemory, Short-TermNeuronsNeuropsychological TestsPrefrontal CortexRatsRats, Sprague-DawleyReceptors, Dopamine D1Sensitivity and SpecificityThionucleotides
2002
Actions of α-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype
Franowicz JS, Arnsten A. Actions of α-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype. Psychopharmacology 2002, 162: 304-312. PMID: 12122489, DOI: 10.1007/s00213-002-1110-6.Peer-Reviewed Original ResearchConceptsSame receptor subtypeReceptor subtypesBlood pressureCognitive improvementHypotensive effectNoradrenergic agonistsRhesus monkeysDose-dependent reversalCognitive-enhancing effectsNon-human primatesIdazoxan doseCognitive enhancementMK-912Same dosesHypotensionLow dosesAgonistsSubtypesPotent antagonistAntagonistMK912Recent evidenceClonidineIdazoxanDoses
2000
The Selective Dopamine D4 Receptor Antagonist, PNU-101387G, Prevents Stress-Induced Cognitive Deficits in Monkeys
Arnsten A, Murphy B, Merchant K. The Selective Dopamine D4 Receptor Antagonist, PNU-101387G, Prevents Stress-Induced Cognitive Deficits in Monkeys. Neuropsychopharmacology 2000, 23: 405-410. PMID: 10989267, DOI: 10.1016/s0893-133x(00)00133-0.Peer-Reviewed Original ResearchConceptsD4 receptor antagonistReceptor mechanismsReceptor antagonistDopamine D1 receptor mechanismsStress-induced cognitive dysfunctionPrefrontal cortexSelective dopamine D4 receptor antagonistSelective D4 receptor antagonistD1 receptor mechanismsDose-related reversalDopamine D4 receptor antagonistCognitive dysfunctionPharmacological stressorHigh dosesLow dosesMemory deficitsCognitive deficitsStress exposureFurther studiesCognitive functioningAntagonistFG7142DosesPreliminary findingsMonkeysThe Alpha-2A-Adrenoceptor Agonist, Guanfacine, Increases Regional Cerebral Blood Flow in Dorsolateral Prefrontal Cortex of Monkeys Performing a Spatial Working Memory Task
Avery R, Franowicz J, Studholme C, van Dyck C, Arnsten A. The Alpha-2A-Adrenoceptor Agonist, Guanfacine, Increases Regional Cerebral Blood Flow in Dorsolateral Prefrontal Cortex of Monkeys Performing a Spatial Working Memory Task. Neuropsychopharmacology 2000, 23: 240-249. PMID: 10942848, DOI: 10.1016/s0893-133x(00)00111-1.Peer-Reviewed Original ResearchMeSH KeywordsAdrenergic alpha-2 Receptor AgonistsAdrenergic alpha-AgonistsAnimalsCerebrovascular CirculationCognitionFemaleGuanfacineImage Processing, Computer-AssistedMacaca mulattaMagnetic Resonance ImagingMemoryPrefrontal CortexSpace PerceptionStimulation, ChemicalTomography, Emission-Computed, Single-PhotonConceptsRegional cerebral blood flowCerebral blood flowPrefrontal cortexDorsolateral prefrontal cortexBlood flowAlpha 2A-adrenoceptorsAuditory association areasSuperior temporal cortexBlood flow tracerSPECT measuresAdrenoceptor agonistsAdrenoceptor stimulationAlpha-2aMemory taskAdrenoreceptor agonistIntravenous cathetersGuanfacine treatmentTemporal cortexRCBF valuesAssociation areasBrain regionsGuanfacineCortexSpatial Working Memory taskCognitive performance
1999
Treatment with the Noradrenergic Alpha-2 Agonist Clonidine, But Not Diazepam, Improves Spatial Working Memory in Normal Young Rhesus Monkeys
Franowicz J, Arnsten A. Treatment with the Noradrenergic Alpha-2 Agonist Clonidine, But Not Diazepam, Improves Spatial Working Memory in Normal Young Rhesus Monkeys. Neuropsychopharmacology 1999, 21: 611-621. PMID: 10516957, DOI: 10.1016/s0893-133x(99)00060-3.Peer-Reviewed Original ResearchMeSH KeywordsAdrenergic alpha-AgonistsAdrenergic alpha-AntagonistsAdrenergic Uptake InhibitorsAnimalsBehavior, AnimalClonidineCognitionDiazepamDose-Response Relationship, DrugFemaleHypnotics and SedativesIdazoxanMacaca mulattaMemoryReaction TimeReceptors, Adrenergic, alpha-2ReserpineSpace PerceptionConceptsAlpha 2 agonist clonidineEffects of clonidineSpatial working memoryChronic reserpine treatmentYoung adult monkeysPrefrontal cortical functionYoung adult humansYoung rhesus monkeysAgonist clonidineReserpine treatmentCortical functionClonidineHuman studiesAdult monkeysHigh dosesLow dosesRhesus monkeysAged monkeysNonhuman primatesDose rangeAdult humansInsufficient dosageConflicting resultsYoung monkeysMonkeysLocal infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys
Mao Z, Arnsten A, Li B. Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biological Psychiatry 1999, 46: 1259-1265. PMID: 10560031, DOI: 10.1016/s0006-3223(99)00139-0.Peer-Reviewed Original ResearchConceptsAlpha-2 adrenoceptorsRat prefrontal cortexPrefrontal cortexAlpha-1 adrenoceptor stimulationAlpha-1 adrenergic agonist phenylephrineAlpha-1 adrenoceptorsAdrenergic agonist phenylephrineDorsolateral prefrontal cortexAgonist phenylephrinePhenylephrine infusionAdrenoceptor stimulationLocal infusionAgonist guanfacineAdrenergic agonistsPrefrontal cortex impairsAdrenoceptorsDelayed-response taskInfusionAlpha 1Rat experimentsStimulationMonkeysGuanfacineSWM functionSWM performance
1998
The α-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys
Franowicz JS, Arnsten A. The α-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 1998, 136: 8-14. PMID: 9537677, DOI: 10.1007/s002130050533.Peer-Reviewed Original ResearchConceptsYoung adult rhesus monkeysAdult rhesus monkeysHigh dosesDorsolateral prefrontal cortical functionRhesus monkeysDose of idazoxanEffects of guanfacinePrefrontal cortical functionAntagonist idazoxanNoradrenergic agonistsCatecholamine depletionMild sedationAdrenergic agonistsCortical functionDrug effectsAged animalsGuanfacineAdrenergic receptorsLow dosesAged monkeysEffective doseIntact animalsIdazoxanDosesYoung animals
1997
The Alpha-1 Adrenergic Agonist, Cirazoline, Impairs Spatial Working Memory Performance in Aged Monkeys
Arnsten A, Jentsch JD. The Alpha-1 Adrenergic Agonist, Cirazoline, Impairs Spatial Working Memory Performance in Aged Monkeys. Pharmacology Biochemistry And Behavior 1997, 58: 55-59. PMID: 9264070, DOI: 10.1016/s0091-3057(96)00477-7.Peer-Reviewed Original ResearchConceptsAlpha-1 adrenergic agonistAdrenergic antagonistsAdrenergic agonistsAlpha-1 adrenergic antagonistAlpha-1 adrenergic receptorsAdditional high affinityGood brain penetranceAlpha 2 receptorsAdrenergic receptor stimulationPrefrontal cortical functionSpatial Working Memory PerformanceBrain penetranceImidazoline receptorsCortical functionNonspecific changesCirazolineControl trialMemory performanceReceptor stimulationAdrenergic receptorsLow dosesRhesus monkeysAged monkeysPrefrontal cortexDrug actionClozapine Reverses the Spatial Working Memory Deficits Induced by FG7142 in Monkeys
Murphy B, Roth R, Arnsten A. Clozapine Reverses the Spatial Working Memory Deficits Induced by FG7142 in Monkeys. Neuropsychopharmacology 1997, 16: 433-437. PMID: 9165499, DOI: 10.1016/s0893-133x(97)00019-5.Peer-Reviewed Original ResearchConceptsMemory deficitsClozapine dosesCognitive deficitsDA receptor stimulationLow clozapine dosesDose-related impairmentPFC cognitive deficitsSpatial Working Memory DeficitsClozapine pretreatmentClozapine reversesAtypical neurolepticsPharmacological stressorDopamine dysregulationReceptor stimulationCognitive functionNonhuman primatesClinical rangeDosesWorking Memory DeficitsClozapineMonkeysDeficitsFG7142SchizophreniaCurrent studyThe effects of 5-HT3 receptor antagonists on cognitive performance in aged monkeys
Arnsten A, Lin C, Van Dyck C, Stanhope K. The effects of 5-HT3 receptor antagonists on cognitive performance in aged monkeys. Neurobiology Of Aging 1997, 18: 21-28. PMID: 8983029, DOI: 10.1016/s0197-4580(96)00162-5.Peer-Reviewed Original ResearchConceptsVisual object discriminationObject discriminationFine motor tasksMotor tasksCognitive-enhancing effectsMemory taskResponse taskCognitive performanceReceptor antagonistEnhanced acquisitionCognitive functionReliable improvementMarmoset researchAged monkeysTaskReversal conditionsWide dose rangeDiscriminationSide effectsLow dosesRhesus monkeysDose rangeAntagonistAcquisitionMonkeys
1996
Dopamine and Spatial Working Memory in Rats and Monkeys: Pharmacological Reversal of Stress-Induced Impairment
Murphy B, Arnsten A, Jentsch J, Roth R. Dopamine and Spatial Working Memory in Rats and Monkeys: Pharmacological Reversal of Stress-Induced Impairment. Journal Of Neuroscience 1996, 16: 7768-7775. PMID: 8922432, PMCID: PMC6579090, DOI: 10.1523/jneurosci.16-23-07768.1996.Peer-Reviewed Original ResearchConceptsRodent prefrontal cortexPrefrontal cortexSpatial working memoryBenzodiazepine inverse agonist FG7142Stress-Induced ImpairmentsWorking memoryCognitive tasksVentral tegmental areaCognitive functioningCognitive deficitsMemory deficitsDopamine neuron cell bodiesD-cycloserineCognitive impairmentMultiple neurotransmitter systemsGlycine/NMDA antagonistsCognitionFG7142Dopamine turnoverTerminal field areasCurrent studyNeurotransmitter systemsDeficitsCortexImpairment
1995
Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys
Arnsten A, Cai J, Steere J, Goldman-Rakic P. Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys. Journal Of Neuroscience 1995, 15: 3429-3439. PMID: 7751922, PMCID: PMC6578230, DOI: 10.1523/jneurosci.15-05-03429.1995.Peer-Reviewed Original ResearchConceptsYoung adult monkeysFine motor tasksFine motor performanceAge-related cognitive declineAdult monkeysCognitive declineMotor performanceAged monkeysD2 dopamine receptor agonistDopamine D2 receptor mechanismsMotor tasksAged monkey brainsD2 receptor mechanismsDopamine receptor agonistsPrefrontal cortical cognitive functionEffects of quinpiroleD2 receptor functionCortical cognitive functionsAge-related lossDelayed response performanceQuinpirole responseDA depletionMotor cortexD2 autoreceptorsPostsynaptic receptors