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 ResearchConceptsKCNQ 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
mGluR2 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
A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation
McKee SA, Potenza MN, Kober H, Sofuoglu M, Arnsten A, Picciotto MR, Weinberger AH, Ashare R, Sinha R. A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. Journal Of Psychopharmacology 2014, 29: 300-311. PMID: 25516371, PMCID: PMC4376109, DOI: 10.1177/0269881114562091.Peer-Reviewed Original ResearchConceptsPlacebo-treated subjectsFunctional magnetic resonance imagingCentral noradrenergic pathwaysPrefrontal cognitive dysfunctionSystolic blood pressureClinical outcome dataAd libitum smokingNovel translational approachStress-induced reinstatementMagnetic resonance imagingNicotine-deprived smokersBlood pressureNoradrenergic pathwaysAgonist guanfacineCognitive dysfunctionTreatment periodTobacco cravingQuit attemptsOutcome dataSmokingComplete abstinenceCortisol levelsTranslational investigationsCigarette useGuanfacine
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
2000
Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats
Birnbaum SG, Podell DM, Arnsten A. Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats. Pharmacology Biochemistry And Behavior 2000, 67: 397-403. PMID: 11164065, DOI: 10.1016/s0091-3057(00)00306-3.Peer-Reviewed Original ResearchConceptsReceptor agonistMemory deficitsAnxiogenic drugsSide effectsAlpha-1 receptor stimulationAlpha-2 adrenoceptor subtypesAlpha-2 receptor agonistCognitive deficitsPrefrontal cortexStress-related neuropsychiatric disordersImidazoline I1 receptor agonistHypotensive side effectsEfficacy of clonidineI1 receptor agonistPrefrontal cognitive deficitsPrefrontal cortical functionClonidine pretreatmentDA turnoverAdrenoceptor agonistsAdrenoceptor subtypesCatecholamine releaseReceptor subtypesCortical functionTherapeutic usefulnessReceptor stimulationGenetics of Childhood Disorders: XVIII. ADHD, Part 2: Norepinephrine Has a Critical Modulatory Influence on Prefrontal Cortical Function
ARNSTEN A, Lombroso P. Genetics of Childhood Disorders: XVIII. ADHD, Part 2: Norepinephrine Has a Critical Modulatory Influence on Prefrontal Cortical Function. Journal Of The American Academy Of Child & Adolescent Psychiatry 2000, 39: 1201-1203. PMID: 10986819, DOI: 10.1097/00004583-200009000-00022.Peer-Reviewed Original Research
1999
Local 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 performanceA role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in the prefrontal cortex
Birnbaum S, Gobeske K, Auerbach J, Taylor J, Arnsten A. A role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in the prefrontal cortex. Biological Psychiatry 1999, 46: 1266-1274. PMID: 10560032, DOI: 10.1016/s0006-3223(99)00138-9.Peer-Reviewed Original ResearchConceptsStress-induced cognitive deficitsPoor attention regulationAlternation performanceSpatial working memoryPFC cognitive functionPrefrontal cortical dysfunctionMotor response timeIntra-PFC infusionsStress-induced deficitsStress-induced impairmentWorking memoryAttention regulationPFC contributeMemory performanceAlternation testingStress researchNeuropsychiatric disordersPrefrontal cortexCognitive deficitsCognitive functionMemory functionMemory impairmentPFC dysfunctionPerseverative patternsPharmacological stressorDevelopment of the Cerebral Cortex: XIV. Stress Impairs Prefrontal Cortical Function
Lombroso P, ARNSTEN A. Development of the Cerebral Cortex: XIV. Stress Impairs Prefrontal Cortical Function. Journal Of The American Academy Of Child & Adolescent Psychiatry 1999, 38: 220-222. PMID: 9951224, DOI: 10.1097/00004583-199902000-00024.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statementsα-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function
Arnsten A, Mathew R, Ubriani R, Taylor J, Li B. α-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function. Biological Psychiatry 1999, 45: 26-31. PMID: 9894572, DOI: 10.1016/s0006-3223(98)00296-0.Peer-Reviewed Original ResearchConceptsPrefrontal cortexCognitive functionPrefrontal cortical cognitive functionCortical cognitive functionsImpairs cognitive functionHigher cortical functionsMemory taskAlpha-1 adrenoceptorsMost antipsychotic medicationsAlternation performanceNoradrenergic turnoverCortical functionPhenylephrine responseAlpha-1 adrenoceptor stimulationNeuropsychiatric disordersAlpha-1 adrenergic antagonistAlpha-1 adrenergic agonistDisordersAntipsychotic medicationAnxietyHigh levelsPhenylephrine infusionAdrenoceptor stimulationAdrenergic antagonistsSecond messenger pathways
1997
Supranormal Stimulation of D1 Dopamine Receptors in the Rodent Prefrontal Cortex Impairs Spatial Working Memory Performance
Zahrt J, Taylor J, Mathew R, Arnsten A. Supranormal Stimulation of D1 Dopamine Receptors in the Rodent Prefrontal Cortex Impairs Spatial Working Memory Performance. Journal Of Neuroscience 1997, 17: 8528-8535. PMID: 9334425, PMCID: PMC6573725, DOI: 10.1523/jneurosci.17-21-08528.1997.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzazepinesDopamineDopamine AgonistsDopamine AntagonistsInfusions, ParenteralMaleMaze LearningMemoryModels, NeurologicalModels, PsychologicalPrefrontal CortexPsychomotor PerformanceRatsRats, Sprague-DawleyReceptors, Dopamine D1Receptors, N-Methyl-D-AspartateSpatial BehaviorStress, PsychologicalConceptsD1 receptor stimulationPrefrontal cortexReceptor stimulationSKF 81297SCH 23390D1 receptorsSupranormal stimulationPFC of ratsD1 receptor mechanismsDA receptor stimulationDose-related impairmentD1 receptor antagonistD1 receptor agonistD1 dopamine receptorsDelayed-alternation performanceMemory functionRecent electrophysiological studiesSpatial Working Memory PerformanceReceptor antagonistReceptor agonistDopamine receptorsReceptor mechanismsElectrophysiological studiesHigh dosesDrug efficacyThe acetylcholine releaser linopirdine increases parietal regional cerebral blood flow in Alzheimer’s disease
van Dyck C, Lin C, Robinson R, Cellar J, Smith E, Nelson J, Arnsten A, Hoffer P. The acetylcholine releaser linopirdine increases parietal regional cerebral blood flow in Alzheimer’s disease. Psychopharmacology 1997, 132: 217-226. PMID: 9292621, DOI: 10.1007/s002130050339.Peer-Reviewed Original ResearchConceptsRegional cerebral blood flowParietal regional cerebral blood flowCerebral blood flowAlzheimer's diseaseAD patientsBlood flowDouble-blind trialWeeks of treatmentAD drug therapyProbable Alzheimer's diseaseParietal association cortexSingle photon emissionPlacebo TIDRCBF abnormalitiesCholinergic drugsDrug therapyHealthy controlsRCBF ratiosPharmacological interventionsHealthy subjectsAssociation cortexPatientsLinopirdineBrain regionsNeuropsychological function
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
Guanfacine Treatment of Comorbid Attention-Deficit Hyperactivity Disorder and Tourette's Syndrome: Preliminary Clinical Experience
CHAPPELL P, RIDDLE M, SCAHILL L, LYNCH K, SCHULTZ R, ARNSTEN A, LECKMAN J, COHEN D. Guanfacine Treatment of Comorbid Attention-Deficit Hyperactivity Disorder and Tourette's Syndrome: Preliminary Clinical Experience. Journal Of The American Academy Of Child & Adolescent Psychiatry 1995, 34: 1140-1146. PMID: 7559307, DOI: 10.1097/00004583-199509000-00010.Peer-Reviewed Original ResearchConceptsYale Global Tic Severity ScaleAttention deficit hyperactivity disorderTourette syndromeContinuous Performance TestHyperactivity disorderOpen-label studyCommon side effectsSeverity of motorComorbid attention deficit hyperactivity disorderSafe alternative therapySignificant decreaseTic Severity ScalePreliminary clinical experienceMajority of subjectsConners' Parent Rating ScaleTransient sedationControlled TrialsAlternative therapiesSedative effectsGuanfacine treatmentPhonic ticsSeverity ScaleSide effectsStimulant medicationTic severityAn Open Trial of Guanfacine in the Treatment of Attention-Deficit Hyperactivity Disorder
Hunt R, Arnsten A, Asbell M. An Open Trial of Guanfacine in the Treatment of Attention-Deficit Hyperactivity Disorder. Journal Of The American Academy Of Child & Adolescent Psychiatry 1995, 34: 50-54. PMID: 7860456, DOI: 10.1097/00004583-199501000-00013.Peer-Reviewed Original ResearchConceptsAttention deficit hyperactivity disorderGreater attentional abilityConners' Parent RatingUse of guanfacineAttentional abilitiesConners' hyperactivityParent ratingsHyperactivity disorderFrustration tolerancePatients' mean scoresSelective binding profileHyperactive childrenLonger excretionGuanfacine treatmentADHDHyperactive behaviorMean scoreSide effectsAlpha-2 noradrenergic agonistPsychiatric outpatientsGuanfacineDouble-blind studyBehavioral changesSedative side effectsOpen trial
1991
Behavioral and receptor binding analysis of the α2-adrenergic agonist, 5-bromo-6 [2-imidazoline-2-YL amino] quinoxaline (UK-14304): evidence for cognitive enhancement at an α2-adrenoceptor subtype
Arnsten A, Leslie FM. Behavioral and receptor binding analysis of the α2-adrenergic agonist, 5-bromo-6 [2-imidazoline-2-YL amino] quinoxaline (UK-14304): evidence for cognitive enhancement at an α2-adrenoceptor subtype. Neuropharmacology 1991, 30: 1279-1289. PMID: 1686301, DOI: 10.1016/0028-3908(91)90024-6.Peer-Reviewed Original Research