Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex
Open accessAbstract
The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed behavior. Moreover, dysregulated prefrontal cognitive dysfunction is associated with multiple psychiatric disorders. Norepinephrine (NE) signaling in the PFC is a critical modulator of prefrontal cognition and is targeted by a variety of drugs used to treat PFC-dependent cognitive dysfunction. Noradrenergic modulation of PFC-dependent cognition is complex, with concentration and receptor-specific actions that are likely dependent on neuronal activity state. Recent studies indicate that within the PFC, noradrenergic α1 and α2 receptors exert unique modulatory actions across distinct cognitive processes that allow for context-dependent modulation of cognition. Specifically, high affinity post-synaptic α2 receptors, engaged at moderate rates of NE release associated with moderate arousal levels, promote working memory. In contrast, lower affinity α1 receptors, engaged at higher rates of release associated with high arousal conditions (e.g. stress), impair working memory performance while promoting flexible attention. While these and other observations were initially interpreted to indicate high rates of NE release promotes the transition from focused to flexible/scanning attention, recent findings indicate that α1 receptors promote both focused and flexible attention. Collectively, these observations indicate that while α2 and α1 receptors in the PFC differentially modulate distinct cognitive processes, this cannot be simply ascribed to differential roles of these receptors in 'focused' vs. 'flexible' cognitive processes. Translationally, this information indicates that: (1) not all tests of prefrontal cognitive function may be appropriate for preclinical programs aimed at specific PFC-dependent disorders and (2) the treatment of specific PFC cognitive deficits may require the differential targeting of noradrenergic receptor subtypes. This article is part of a Special Issue entitled SI: Noradrenergic System.
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Cites
Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299 · see citing works
Nucleus locus ceruleus: new evidence of anatomical and physiological specificity
Foote, S. L., Bloom, F. E., & Aston-Jones, G. (1983) · Physiological Reviews · doi:10.1152/physrev.1983.63.3.844 · Cited by 1,901 · see citing works
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Dalley, J. W., Cardinal, R. N., & Robbins, T. W. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.09.006 · Cited by 1,329 · see citing works
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
Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions
Arnsten, A. F. T., & Li, B.-M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.08.019 · Cited by 948 · see citing works
Wang, M., Ramos, B. P., Paspalas, C. D., Shu, Y., Simen, A., Duque, A., Vijayraghavan, S., Brennan, A., Dudley, A., Nou, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.015 · Cited by 672 · see citing works
Kuczenski, R., & Segal, D. S. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68052032.x · Cited by 623 · see citing works
Berridge, C. W., Devilbiss, D. M., Andrzejewski, M. E., Arnsten, A. F. T., Kelley, A. E., Schmeichel, B., Hamilton, C., & Spencer, R. C. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.04.022 · Cited by 617 · see citing works
Self-citationArnsten, 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
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 · cited 1× · see citing works
“The role of PFC NE in cognition has been extensively studied using delayed response tests of working memory (Arnsten, 2000, 2011).”
Arnsten, A. F., & Dudley, A. G. (2005) · Behavioral and Brain Functions · doi:10.1186/1744-9081-1-2 · Cited by 363 · see citing works
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
Kuczenski, R., & Segal, D. S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-16-07264.2002 · Cited by 316 · see citing works
Gamo, N. J., Wang, M., & Arnsten, A. F. T. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.06.015 · Cited by 232 · see citing works
Through the looking glass: Differential noradenergic modulation of prefrontal cortical function
Arnsten, A. F. T. (2000) · Neural Plasticity · doi:10.1155/np.2000.133 · Cited by 229 · see citing works
Li, B.-M., & Mei, Z.-T. (1994) · Behavioral and Neural Biology · doi:10.1016/s0163-1047(05)80034-2 · Cited by 186 · 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
Self-citationThe beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys
Ramos, B. P., Colgan, L., Nou, E., Ovadia, S., Wilson, S. R., & Arnsten, A. F. T. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.05.022 · Cited by 147 · see citing works
Locomotor hyperactivity induced by blockade of prefrontal cortical α2-adrenoceptors in monkeys
Ma, C.-L., Arnsten, A. F. T., & Li, B.-M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.11.004 · Cited by 96 · see citing works
Flagged first, then by citations
Research works printed but not linked: 53
- Alsene KM Bakshi VP 2011 Pharmacological stimulation of locus coeruleus reveals a new antipsychotic-responsive pathway for deficient sensorimotor gating Neuropsychopharmacology 36 1656 67 21508929 PMC3138657
- Alsene KM Rajbhandari AK Ramaker MJ Bakshi VP 2011 Discrete forebrain neuronal networks supporting noradrenergic regulation of sensorimotor gating Neuropsychopharmacology 36 1003 14 21248721 PMC3077269
- Arnsten AF Steere JC Hunt RD 1996 The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention- deficit hyperactivity disorder Arch Gen Psychiatry 53 448 455 8624188
- Arnsten AF 2010 The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder Expert Rev Neurother 10 1595 605 20925474 PMC3143019
- Arnsten AFT Castellanos FX 2002 Neurobiology of attention regulation and its disorders Textbook of Child and Adolescent Psychopharmacology Vol Martin A Scahill L Charney D Leckman J Oxford University Press New York 99 109
- Berridge C Devilbiss D Spencer R Schmeichel B Arnsten A Schmeichel B 2012a Attention Deficit Hyperactivity Disorder Translational Neuroscience: Applications in Psychiatry, Neurology and Neurodevelopmental Disorders Vol Barrett JCJ Williams M Cambridge University Press Cambridge
- Berridge C Shumsky JS Andrzejewski ME McGaughy J Spencer RC Devilbiss D Waterhouse B 2012b Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of Noradrenergic α1- vs. α2-Receptors Biol Psychiatry 71 467 473 21890109 PMC3233638
- Berridge CW Waterhouse BD 2003 The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes Brain Res Brain Res Rev 42 33 84 12668290
- Berridge CW 2006 Neural substrates of psychostimulant-induced arousal Neuropsychopharmacology 31 2332 2340 16855535
- Berridge CW Devilbiss DM 2011 Psychostimulants as Cognitive Enhancers: The Prefrontal Cortex, Catecholamines, and Attention-Deficit/Hyperactivity Disorder Biol Psychiatry 69 e101 e111 20875636 PMC3012746
- Birnbaum S Gobeske KT Auerbach J Taylor JR Arnsten AF 1999 A role for norepinephrine in stress-induced cognitive deficits: alpha-1- adrenoceptor mediation in the prefrontal cortex Biol Psychiatry 46 1266 1274 10560032
- Birrell JM Brown VJ 2000 Medial frontal cortex mediates perceptual attentional set shifting in the rat J Neurosci 20 4320 4 10818167 PMC6772641
- Devilbiss DM Berridge CW 2008 Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness Biol Psychiatry 64 626 635 18585681 PMC2603602
- Drouin C Page M Waterhouse B 2006 Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats J Neurophysiol 96 622 632 16687613
- Furth KE Mastwal S Wang KH Buonanno A Vullhorst D 2013 Dopamine, cognitive function, and gamma oscillations: role of D4 receptors Front Cell Neurosci 7 102 23847468 PMC3698457
- Geyer MA Krebs-Thomson K Braff DL Swerdlow NR 2001 Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review Psychopharmacology (Berl) 156 117 54 11549216
- Goldman-Rakic PS 1995 Cellular basis of working memory Neuron 14 477 485 7695894
- Greenhill LL 2001 Clinical effects of stimulant medication in ADHD Stimulant Drugs and ADHD: Basic and Clinical Neuroscience Vol Solanto MV Arnsten AFT Castellanos FX Oxford University Press New York 31 71
- Haber SN 2003 The primate basal ganglia: parallel and integrative networks J Chem Neuroanat 26 317 30 14729134
- Haber SN Calzavara R 2009 The cortico-basal ganglia integrative network: the role of the thalamus Brain Res Bull 78 69 74 18950692 PMC4459637
- Kuczenski R Segal DS Aizenstein ML 1991 Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics J Neurosci 11 2703 2712 1715389 PMC6575248
- Kuczenski R Segal DS 2001 Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine J Pharmacol Exp Ther 296 876 883 11181919
- Lapiz MD Morilak DA 2006 Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability Neuroscience 137 1039 1049 16298081
- Lewis DA Morrison JH 1989 Noradrenergic innervation of monkey prefrontal cortex: a dopamine-beta-hydroxylase immunohistochemical study J Comp Neurol 282 317 30 2715385
- Ma CL Qi XL Peng JY Li BM 2003 Selective deficit in no-go performance induced by blockade of prefrontal cortical alpha 2-adrenoceptors in monkeys Neuroreport 14 1013 6 12802193
- MacDonald E Kobilka BK Scheinin M 1997 Gene targeting--homing in on alpha 2-adrenoceptor-subtype function Trends Pharmacol Sci 18 211 219 9227000
- Marek GJ Aghajanian GK 1999 5-HT2A receptor or α1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex Eur J Pharmacology 367 197 206 10078993
- McGaughy J Ross RS Eichenbaum H 2008 Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting Neuroscience 153 63 71 18355972 PMC2615225
- Navarra R Graf R Huang Y Logue S Comery T Hughes Z Day M 2008 Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test Prog Neuropsychopharmacol Biol Psychiatry 32 34 41 17714843
- Nicholas AP Pieribone V Hokfelt T 1993a Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: an in situ hybridization study J Comp Neurol 328 575 594 8381444
- Nicholas AP Pieribone VA Hokfelt T 1993b Cellular localization of messenger RNA for beta-1 and beta-2 adrenergic receptors in rat brain: an in situ hybridization study Neuroscience 56 1023 1039 8284033
- Owen AM Roberts AC Polkey CE Sahakian BJ Robbins TW 1991 Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man Neuropsychologia 29 993 1006 1762678
- Pieribone VA Nicholas AP Dagerlind A Hokfelt T 1994 Distribution of alpha 1 adrenoceptors in rat brain revealed by in situ hybridization experiments utilizing subtype-specific probes J Neurosci 14 4252 4268 8027777 PMC6577046
- Price JL Carmichael ST Drevets WC 1996 Networks related to the orbital and medial prefrontal cortex; a substrate for emotional behavior? Prog Brain Res 107 523 36 8782540
- Rajkowski J Kubiak P Aston-Jones G 1994 Locus coeruleus activity in monkey: phasic and tonic changes are associated with altered vigilance Brain Res Bull 35 607 616 7859118
- Ramos BP Colgan LA Nou E Arnsten AF 2008 Beta2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals Neurobiol Aging 29 1060 1069 17363115 PMC3154024
- Rapoport JL Buchsbaum MS Weingartner H Zahn TP Ludlow C Mikkelsen EJ 1980 Dextroamphetamine - Its Cognitive and Behavioral-Effects in Normal and Hyperactive Boys and Normal Men Arch Gen Psychiatry 37 933 943 7406657
- Rapoport JL Inoff-Germain G 2002 Responses to methylphenidate in Attention-Deficit/Hyperactivity Disorder and normal children: update 2002 J Atten Disord 6 S57 S60 12685519
- Robbins TW 1996 Dissociating executive functions of the prefrontal cortex Philos Trans R Soc Lond B Biol Sci 351 1463 70 discussion 1470-1 8941958
- Snyder K Wang WW Han R McFadden K Valentino RJ 2012 Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility Neuropsychopharmacology 37 520 30 21993205 PMC3242313
- Solanto MV 1998 Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration Behav Brain Res 94 127 152 9708845
- Spencer RC Klein RM Berridge CW 2012 Psychostimulants act within the prefrontal cortex to improve cognitive function Biol Psychiatry 72 221 7 22209638 PMC3319517
- Sprague RL Sleator EK 1977 Methylphenidate in hyperkinetic children: differences in dose effects on learning and social behavior Science 198 1274 6 337493
- Swerdlow NR Taaid N Oostwegel JL Randolph E Geyer MA 1998 Towards a cross-species pharmacology of sensorimotor gating: effects of amantadine, bromocriptine, pergolide and ropinirole on prepulse inhibition of acoustic startle in rats Behav Pharmacol 9 389 96 9832924
- Swerdlow NR Braff DL Geyer MA 1999 Cross-species studies of sensorimotor gating of the startle reflex Ann N Y Acad Sci 877 202 16 10415651
- Tannock R Schachar RJ Carr RP Logan GD 1989 Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children Pediatrics 84 648 657 2780127
- Usher M Cohen JD Servan-Schreiber D Rajkowski J Aston-Jones G 1999 The role of locus coeruleus in the regulation of cognitive performance Science 283 549 554 9915705
- Van Tol HH Bunzow JR Guan HC Sunahara RK Seeman P Niznik HB Civelli O 1991 Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine Nature 350 610 614 1840645
- Vertes RP 2004 Differential projections of the infralimbic and prelimbic cortex in the rat Synapse 51 32 58 14579424
- Wilens TE Biederman J Lerner M 2004 Effects of once-daily osmotic-release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder: results from a one-year follow-up study J Clin Psychopharmacol 24 36 41 14709945
- Yuen EY Zhong P Li X Wei J Yan Z 2013 Restoration of glutamatergic transmission by dopamine D4 receptors in stressed animals J Biol Chem 288 26112 20 23884421 PMC3764814
- Zhang Z Cordeiro Matos S Jego S Adamantidis A Seguela P 2013 Norepinephrine drives persistent activity in prefrontal cortex via synergistic alpha1 and alpha2 adrenoceptors PLoS One 8 e66122 23785477 PMC3681776
- Zhong P Yan Z 2014 Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons Cereb Cortex PMC4677974 25146372
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“It is widely accepted that clinically relevant doses improve and supra-clinical doses impair working memory (41).”
Background
- Authors
- Berridge, C. W., & Spencer, R. C.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Berridge, Craig W.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 1641
- Issue
- Pt B
- Pages
- 189-196
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC4876052
- OpenAlex
- W2177596836
- Cited by
- 112
- References
- 19
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 10 · 2023: 13 · 2022: 11 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 7 · 2017: 9 · 2016: 2
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- PHS (MH098631, MH081843)
- University of Wisconsin-Madison Graduate School
- 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 and Behavioral Psychology Studies
- Keywords
- norepinephrine, alpha2-adrenoceptors, alpha1-adrenoceptors, prefrontal cortex, noradrenergic modulation, working memory, focused attention, arousal, stress, cognitive impairment, mental illness
- MeSH terms
- Animals, Attention, Cognition, Humans, Memory, Short-Term, Prefrontal Cortex, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, alpha-2, Sensory Gating
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