Through the looking glass: Differential noradenergic modulation of prefrontal cortical function

Arnsten, Amy F. T.

doi:10.1155/np.2000.133

Cited by 229Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchNeural dynamics and brain function

Through the looking glass: Differential noradenergic modulation of prefrontal cortical function

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Arnsten, Amy F. T.·2000·Neural Plasticity

DOI 10.1155/np.2000.133PMC PMC2565372

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Abstract

Ghosts rising off the lakeIn to moonlight In between Never so alive Norepinephrine (NE) facilitates the functioning of many brain areas, otten by increasing "signals" relative to "noise".In most brain regions, NE enhances neural processing through actions at beta and alpha-1 adrenergic receptors.This review will provide a brief overview of the receptor mechanisms influencing subcortical and posterior cortical functions and contrast these actions with the very different mechanisms by which NE modulates the working memory functions of the prefrontal cortex (PFC; Fig. 1). BETA-AND ALPHA-I-ADRENOCEPTOR STIMULATION ENHANCE POSTERIOR CORTICAL AND SUBCORTICAL FUNCTIONSNE has widespread effects on arousal state, stimulus processing, and plasticity including long-term memory consolidation.Most of these NE actions involve beta adrenergic mechanisms, although alpha-1 receptor stimulation also has important effects on excitability and cortical

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Norepinephrine has the highest affinity for α2-receptors, with lower affinity for α1- and β-receptors.
“Among noradrenergic receptors, NE has the highest affinity for α2-receptors, with lower affinity for α1- and β-receptors (Arnsten, 2000).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Arnsten, 2000
Norepinephrine has the highest affinity for α2 adrenergic receptors and lower affinity for α1 and β receptors.
“Norepinephrine has the highest affinity for α2 adrenergic receptors and lower affinity for α1 and β receptors (34).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [34]
The physiological stress response, indexed by glucocorticoids and catecholamines, is related to distinct cognitive domains including declarative memory and executive functions.
“It is also well established that the physiological response to stress, as indicated by levels of neuroendocrine hormones, glucocorticoids and catecholamines, is related to distinct aspects of cognition, including declarative memory as well as executive functions (Arnsten, 2000; Diamond, Campbell, Park, Halonen, & Zoladz, 2007).”
From Salivary cortisol mediates effects of poverty and parenting on executive functions in early childhood (2011) · cites this paper as Arnsten, 2000
The associations are consistent with neurobiological models linking early experience with HPA axis development and stress hormones with cognition, particularly executive functions.
“These associations are consistent with well defined neurobiological models linking early experience with the development of the HPA axis component of the stress response system (Meaney & Szyf, 2005) and linking stress and stress hormones with cognition, particularly executive functions (Arnsten, 2000; Lupien, Maheu, Tu, Fiocco, & Shramek, 2007).”
From Salivary cortisol mediates effects of poverty and parenting on executive functions in early childhood (2011) · cites this paper as Arnsten, 2000
Norepinephrine levels shape neural responses: moderate arousal promotes prefrontal activity for reflective responses, while high levels reduce prefrontal activity and increase activity in reactive, automatized brain areas.
“In this way, levels of NE act to influence the neural response to stimulation, promoting neural activity in PFC associated with reflective and reasoned responses to stimulation at moderate levels of arousal, whereas at high levels, NE reduces neural activity in PFC and increases neural activity in brain areas associated with reactive, automatized responses to stimulation (Arnsten, 2000).”
From Stress and the development of self-regulation in context (2010) · cites this paper as Arnsten, 2000

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Orienting and reorienting: the locus coeruleus mediates cognition through arousal
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Hyperpolarization-Activated Cation Channels: From Genes to Function
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The Neuropsychopharmacology of Fronto-Executive Function: Monoaminergic Modulation
Robbins, T. W., & Arnsten, A. F. T. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.051508.135535 · Cited by 957 · see citing works
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Dynamic adaptation of large-scale brain networks in response to acute stressors
Hermans, E. J., Henckens, M. J. A. G., Joëls, M., & Fernández, G. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.03.006 · Cited by 936 · see citing works
Child development in the context of adversity: Experiential canalization of brain and behavior.
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Locus coeruleus: a new look at the blue spot
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Tourette's syndrome
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Adrenergic pharmacology and cognition: Focus on the prefrontal cortex
Ramos, B. P., & Arnsten, A. F. T. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.11.006 · Cited by 641 · see citing works
Self-citation
Salivary cortisol mediates effects of poverty and parenting on executive functions in early childhood
Blair, C., Granger, D. A., Willoughby, M., Mills-Koonce, R., Cox, M., Greenberg, M. T., Kivlighan, K. T., Fortunato, C. K., & the FLP Investigators (2011) · Child Development · doi:10.1111/j.1467-8624.2011.01643.x · Cited by 579 · see citing works
ERS/ATS statement on interventional pulmonology
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Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses
Arnsten, A. F. T., Wang, M. J., & Paspalas, C. D. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.038 · Cited by 538 · see citing works
Self-citation
Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks
Arnsten, A. F. T. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.01.027 · Cited by 493 · see citing works
Self-citation
Noradrenaline and Dopamine Neurons in the Reward/Effort Trade-Off: A Direct Electrophysiological Comparison in Behaving Monkeys
Varazzani, C., San‐Galli, A., Gilardeau, S., & Bouret, S. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0454-15.2015 · Cited by 446 · see citing works
HCN channels: Structure, cellular regulation and physiological function
Wahl‐Schott, C., & Biel, M. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8525-0 · Cited by 438 · see citing works
Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments
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Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders
Arnsten, A. F. T., & Pliszka, S. R. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.01.020 · Cited by 383 · see citing works
Self-citation
The effects of stress exposure on prefrontal cortex: Translating basic research into successful treatments for post-traumatic stress disorder
Arnsten, A. F. T., Raskind, M. A., Taylor, F. B., & Connor, D. F. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2014.10.002 · Cited by 381 · see citing works
Self-citation
Stress and the development of self-regulation in context
Blair, C. (2010) · Child Development Perspectives · doi:10.1111/j.1750-8606.2010.00145.x · Cited by 379 · see citing works
“neural activity in PFC associated with reflective and reasoned responses to stimulation at moderate levels of arousal, whereas at high levels, NE reduces neural activity in PFC and increases neural activity in brain areas associated with reactive, automatized responses to stimulation (Arnsten, 2000).”
Background
Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices
Chandler, D. J., Gao, W.-J., & Waterhouse, B. D. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320827111 · Cited by 341 · see citing works
The Noradrenergic 2 Agonist Clonidine Modulates Behavioural and Neuroanatomical Correlates of Human Attentional Orienting and Alerting
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Neuronal Mechanisms Underlying Attention Deficit Hyperactivity Disorder: The Influence of Arousal on Prefrontal Cortical Function
Brennan, A. R., & Arnsten, A. F. T. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.007 · Cited by 267 · see citing works
Self-citation
Neurocognitive development in socioeconomic context: Multiple mechanisms and implications for measuring socioeconomic status
Ursache, A., & Noble, K. G. (2015) · Psychophysiology · doi:10.1111/psyp.12547 · Cited by 252 · see citing works
Stress-Induced Dendritic Remodeling in the Prefrontal Cortex is Circuit Specific
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Modulators in concert for cognition: Modulator interactions in the prefrontal cortex
Briand, L. A., Gritton, H., Howe, W. M., Young, D. A., & Sarter, M. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.06.007 · Cited by 216 · see citing works
ADHD and the Prefrontal Cortex
Arnsten, A. F. T. (2009) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2009.01.018 · Cited by 220 · see citing works
Self-citation
Noradrenergic Modulation of Cognition in Health and Disease
Borodovitsyna, O., Flamini, M. D., & Chandler, D. J. (2017) · Neural Plasticity · doi:10.1155/2017/6031478 · Cited by 210 · see citing works
Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine
Cools, R., & Arnsten, A. F. T. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01100-8 · Cited by 206 · see citing works
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Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders
Sacco, K. A., Bannon, K. L., & George, T. P. (2004) · Journal of Psychopharmacology · doi:10.1177/0269881104047273 · Cited by 201 · see citing works
Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction
Shansky, R. M., Glavis-Bloom, C., Lerman, D., McRae, P., Benson, C., Miller, K., Cosand, L., Horvath, T. L., & Arnsten, A. F. T. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001435 · Cited by 200 · see citing works
Self-citation
Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness
Arnsten, A. F. T. (2007) · Cerebral Cortex · doi:10.1093/cercor/bhm033 · Cited by 200 · see citing works
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Noradrenergic modulation of cognition: Therapeutic implications
Chamberlain, S. R., & Robbins, T. W. (2013) · Journal of Psychopharmacology · doi:10.1177/0269881113480988 · Cited by 193 · see citing works
Role of adrenoceptor subtypes in memory consolidation
Gibbs, M. E., & Summers, R. J. (2002) · Progress in Neurobiology · doi:10.1016/s0301-0082(02)00023-0 · Cited by 175 · see citing works
The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex
Spencer, R. C., Devilbiss, D. M., & Berridge, C. W. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.09.013 · Cited by 164 · see citing works
Noradrenergic dysregulation in the pathophysiology of PTSD
Hendrickson, R. C., & Raskind, M. A. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.05.014 · Cited by 168 · see citing works
Post-traumatic stress disorder and declarative memory functioning: a review
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New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons
Chandler, D. J., Waterhouse, B. D., & Gao, W. (2014) · Frontiers in Neural Circuits · doi:10.3389/fncir.2014.00053 · Cited by 139 · see citing works
Locus coeruleus-norepinephrine modulation of sensory processing and perception: A focused review
McBurney-Lin, J., Lu, J., Zuo, Y., & Yang, H. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.06.009 · Cited by 137 · see citing works
Molecular modulation of prefrontal cortex: Rational development of treatments for psychiatric disorders.
Gamo, N. J., & Arnsten, A. F. T. (2011) · Behavioral Neuroscience · doi:10.1037/a0023165 · Cited by 124 · see citing works
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Psychopharmacological approaches to modulating attention in the five-choice serial reaction time task: implications for schizophrenia
Chudasama, Y., & Robbins, T. W. (2004) · Psychopharmacology · doi:10.1007/s00213-004-1805-y · Cited by 121 · see citing works
Want to Optimize Executive Functions and Academic Outcomes? Simple, Just Nourish the Human Spirit
Diamond, A. D. (2013) · Wiley eBooks · doi:10.1002/9781118732373.ch7 · Cited by 123 · see citing works
A developmental perspective on the regulation of arousal states
Mayes, L. C. (2000) · Seminars in Perinatology · doi:10.1053/sper.2000.9121 · Cited by 116 · see citing works
A dopamine gradient controls access to distributed working memory in the large-scale monkey cortex
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Divergent endocrine abnormalities in melancholic and atypical depression: clinical and pathophysiologic implications
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Molecular activity underlying working memoryPreprint
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Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex
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Simultaneous blockade of dopamine and noradrenaline reuptake promotes disadvantageous decision making in a rat gambling task
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Evidence for Broad Versus Segregated Projections from Cholinergic and Noradrenergic Nuclei to Functionally and Anatomically Discrete Subregions of Prefrontal Cortex
Chandler, D. J., & Waterhouse, B. D. (2012) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2012.00020 · Cited by 99 · see citing works
Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders
Sacco, K. A., Bannon, K. L., & George, T. P. (2004) · Journal of Psychopharmacology · doi:10.1177/026988110401800403 · Cited by 100 · see citing works
Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited
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Children’s Cognitive Performance and Selective Attention Following Recent Community Violence
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Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System
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Is there an acute exercise-induced physiological/biochemical threshold which triggers increased speed of cognitive functioning? A meta-analytic investigation
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The Human Frontal Lobes and Frontal Network Systems: An Evolutionary, Clinical, and Treatment Perspective
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Neuroplasticity Regulation by Noradrenaline in Mammalian Brain
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The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder
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The norepinephrine system affects specific neurophysiological subprocesses in the modulation of inhibitory control by working memory demands
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Declarative Memory after Stress in Humans: Differential Involvement of the β-Adrenergic and Corticosteroid Systems
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Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations
Chandler, D. J. (2015) · Brain Research · doi:10.1016/j.brainres.2015.11.022 · Cited by 79 · see citing works
Molecular Influences on Working Memory Circuits in Dorsolateral Prefrontal Cortex
Arnsten, A. F. T., & Jin, L. E. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-420170-5.00008-8 · Cited by 79 · see citing works
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Context-dependent relationships between locus coeruleus firing patterns and coordinated neural activity in the anterior cingulate cortex
Joshi, S., & Gold, J. I. (2022) · eLife · doi:10.7554/elife.63490 · Cited by 71 · see citing works
Arousal Regulation, Emotional Flexibility, Medial Amygdala Function, and the Impact of Early Experience: Comments on the Paper of Lewis et al.
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Neuroimaging tools to rate regional atrophy, subcortical cerebrovascular disease, and regional cerebral blood flow and metabolism: consensus paper of the EADC
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Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing
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Genetics of Childhood Disorders: XVIII. ADHD, Part 2: Norepinephrine Has a Critical Modulatory Influence on Prefrontal Cortical Function
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Prefrontal modulation of anxiety through a lens of noradrenergic signaling
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Relation of Locus Coeruleus Neurons in Monkeys to Pavlovian and Operant Behaviors
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Psychostimulants Act Within the Prefrontal Cortex to Improve Cognitive Function
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Preschoolers' Executive Function: Importance, Contributors, Research Needs and Assessment Options
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Executive Functions: Formative Versus Reflective Measurement
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Molecular mechanisms of working memory
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Anatomically and functionally distinct locus coeruleus efferents mediate opposing effects on anxiety-like behavior
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Dual contributions of noradrenaline to behavioural flexibility and motivation
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The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion
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The ethics of elective psychopharmacology
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Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects
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Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction
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Pharmacological evidence for the implication of noradrenaline in effort
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Noradrenaline in the aging brain: Promoting cognitive reserve or accelerating Alzheimer's disease?
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Reduced Frontal Nogo-N2 With Uncompromised Response Inhibition During Transcutaneous Vagus Nerve Stimulation—More Efficient Cognitive Control?
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On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists
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Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate
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Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype
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Memory systems in the chick: regional and temporal control by noradrenaline.
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Time-dependent effects of acute stress on working memory performance: A systematic review and hypothesis
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Household Chaos Moderates the Link between Maternal Attribution Bias and Parenting
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A Neuroeconomic Framework for Creative Cognition
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A mechanistic model for individualised treatment of anxiety disorders based on predictive neural biomarkers
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Working memory relates to individual differences in speech category learning: Insights from computational modeling and pupillometry
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Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline
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Chronic Social Defeat Stress Modulates Dendritic Spines Structural Plasticity in Adult Mouse Frontal Association Cortex
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Pharmacogenetics of Addiction Therapy
Nielsen, D. A., Nielsen, E. M., Dasari, T., & Spellicy, C. J. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-0956-8_15 · Cited by 31 · see citing works

Authors: Arnsten, A. F. T.
Affiliations: Yale University (US)
Corresponding author: Arnsten, Amy F. T.
ORCID: Arnsten, Amy F. T.
Venue: Neural Plasticity
Publisher: Wiley
Published: 2000-01
Volume: 7
Issue: 1-2
Pages: 133-146
ISSN: 1687-5443 (ISSN-L)
2090-5904
DOI: 10.1155/np.2000.133
PMC: PMC2565372
OpenAlex: W2012804469
Cited by: 229
References: 80
Citations by year: 2026: 9 · 2025: 8 · 2024: 9 · 2023: 11 · 2022: 15 · 2021: 14 · 2020: 16 · 2019: 10 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 10 · 2014: 16 · 2013: 13 · 2012: 10
FWCI: 0.39
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/3.0/ (vor)
Locations: Neural Plasticity (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute on Aging (AG06036)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords: norepinephrine, prefrontal cortex, beta-adrenergic receptors, alpha1-adrenoceptors, working memory, arousal, signal-to-noise ratio improvement, long-term memory consolidation, cortical excitability
MeSH terms: Adaptation, Psychological, Animals, Humans, Memory, Norepinephrine, Receptors, Adrenergic, alpha, Stress, Physiological, Prefrontal Cortex

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