Amy F. T. Arnsten, PhD
Professor of Neuroscience and of Psychology; Member, Kavli Institute of Neuroscience at Yale University
Research Interests
Aging; Alzheimer Disease; Behavioral Sciences; Psychology, Child; Mental Health; Neurobiology; Neurosciences; Stress Disorders, Post-Traumatic; Prefrontal Cortex; Cognitive Science
Public Health Interests
Aging; Alzheimer's Disease; Child Mental Health; Post-Traumatic Stress Disorder; Psychological Trauma; Schizophrenia
Research Organizations
Interdepartmental Neuroscience Program
WHRY Pilot Project Program Investigators
Research Summary
The Arnsten lab studies molecular influences on higher cognitive function, with the aim of developing rational therapies for mental illness and for age-related cognitive disorders such as Alzheimer's Disease. The work focuses on the prefrontal cortex, a highly evolved brain region that creates our "Mental Sketchpad", allowing us abstract reasoning, high order decision-making, working memory, and thoughtful regulation of attention, behavior and emotion (including inhibition of inappropriate thoughts, actions and feelings). The Arnsten lab has discovered powerful chemical signaling pathways that can impair prefrontal function, e.g. when we are stressed, as well as protective pathways that maintain strong cognitive function. These pathways are altered by normal aging, and can be genetically altered in mental illness. Based on research in the Arnsten lab, two medications have been developed for human use: guanfacine (Intuniv) for the treatment of Attention Deficit Hyperactivity Disorder, and prazosin for the treatment of Post-Traumatic Stress Disorder.
Specialized terms: Molecular influences on higher cognitive function
Extensive Research Description
The Arnsten Lab studies molecular influences on the higher cognitive functions of the prefrontal cortex (PFC), with the overarching goal of developing rational treatments for cognitive disorders and mental illness. The lab uses a multi-disciplinary approach to understand mechanisms influencing working memory at the cellular and behavioral levels. Research has focused on how the arousal pathways rapidly alter PFC network strength through intracellular signaling mechanisms, a process termed Dynamic Network Connectivity. Our data explain how exposure to stress causes the rapid loss of PFC cognitive abilities, and how genetic mutations in molecules that regulate these pathways can lead to symptoms of mental illness. Dysregulation of these pathways with advancing age leads to loss of neuronal firing, cognitive impairments,and increased vulnerability for degeneration. Understanding these mechanisms has led to successful new treatments for patients with PFC dysfunction, including medications for Attention Deficit Hyperactivity Disorder, Post-Traumatic Stress Disorder and a potential treatment for schizophrenia and bipolar disorder.
Selected Publications
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Nicotinic a7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex
Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. (2013) Nicotinic a7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci USA 110:12078-83.
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NMDA 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. (2013) NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77:736-49.
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Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses
Arnsten AF, Wang MJ, Paspalas CD. (2012) Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76:223-39.
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Dynamic Network Connectivity: A new form of neuroplasticity
Arnsten AFT, Paspalas CD, Gamo NJ, Yang Y, Wang M. Dynamic Network Connectivity: A new form of neuroplasticity. Trends in Cognitive Sciences, 4: 365-75, 2010.
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Stress signalling pathways that impair prefrontal cortex structure and function
Stress signalling pathways that impair prefrontal cortex structure and function. Arnsten AF. Nat Rev Neurosci. 2009 Jun;10(6):410-22. Review. PMID: 19455173 [PubMed - indexed for MEDLINE]
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Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan, S., Wang, M., Birnbaum, S.G., Bruce, C.J., Williams, G.V., and Arnsten, A.F.T. (2007). Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nature Neurosci. 10:376-84.
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Alpha-2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex
Wang, M., et al. (2007). Alpha-2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397-410.
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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. Proc Natl Acad Sci U S A 111:5036-41, 2014.
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Stress weakens prefrontal networks: molecular insults to higher cognition.
Arnsten AF. Nat Neurosci.;18:1376-85
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Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders.
Arnsten AF, Wang M, Paspalas CD. Pharmacol Rev. 67:681-96
Full List of PubMed Publications
- Castonguay D, Dufort-Gervais J, Ménard C, Chatterjee M, Quirion R, Bontempi B, Schneider JS, Arnsten AFT, Nairn AC, Norris CM, Ferland G, Bézard E, Gaudreau P, Lombroso PJ, Brouillette J: The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. Curr Biol. 2018 Apr 2; 2018 Mar 22. PMID: 29576474
- Yang ST, Wang M, Paspalas CD, Crimins JL, Altman MT, Mazer JA, Arnsten AFT: Core Differences in Synaptic Signaling Between Primary Visual and Dorsolateral Prefrontal Cortex. Cereb Cortex. 2018 Apr 1. PMID: 29351585
- Datta D, Arnsten AFT: Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia. ACS Chem Neurosci. 2018 Mar 1; 2018 Mar 1. PMID: 29470055
- Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AFT, Paspalas CD: mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks. Cereb Cortex. 2018 Mar 1. PMID: 28108498
- Paspalas CD, Carlyle BC, Leslie S, Preuss TM, Crimins JL, Huttner AJ, van Dyck CH, Rosene DL, Nairn AC, Arnsten AFT: The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology. Alzheimers Dement. 2017 Dec 11; 2017 Dec 11. PMID: 29241829
- Arnsten AFT, Lee D, Pittenger C: Risky Business: The Circuits that Impact Stress-Induced Decision-Making. Cell. 2017 Nov 16. PMID: 29149614
- Morozov YM, Datta D, Paspalas CD, Arnsten AFT: Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex. Neurobiol Aging. 2017 Mar; 2016 Dec 10. PMID: 28027494
- Arnsten AF, Girgis RR, Gray DL, Mailman RB: Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry. 2017 Jan 1; 2016 Jan 18. PMID: 26946382
- Krystal JH, Abi-Dargham A, Akbarian S, Arnsten AFT, Barch DM, Bearden CE, Braff DL, Brown ES, Bullmore ET, Carlezon WA Jr, Carter CS, Cook EH Jr, Daskalakis ZJ, DiLeone RJ, Duman RS, Grace AA, Hariri AR, Harrison PJ, Hiroi N, Kenny PJ, Kleinman JE, Krystal AD, Lewis DA, Lipska BK, Marder SR, Mason GF, Mathalon DH, McClung CA, McDougle CJ, McIntosh AM, McMahon FJ, Mirnics K, Monteggia LM, Narendran R, Nestler EJ, Neumeister A, O'Donovan MC, Öngür D, Pariante CM, Paulus MP, Pearlson G, Phillips ML, Pine DS, Pizzagalli DA, Pletnikov MV, Ragland JD, Rapoport JL, Ressler KJ, Russo SJ, Sanacora G, Sawa A, Schatzberg AF, Shaham Y, Shamay-Tsoory SG, Sklar P, State MW, Stein MB, Strakowski SM, Taylor SF, Turecki G, Turetsky BI, Weissman MM, Zachariou V, Zarate CA Jr, Zubieta JK: Constance E. Lieber, Theodore R. Stanley, and the Enduring Impact of Philanthropy on Psychiatry Research. Biol Psychiatry. 2016 Jul 15. PMID: 27346079
- Arnsten AF, Murray JD, Seo H, Lee D: Ketamine's Antidepressant Actions: Potential Mechanisms in the Primate Medial Prefrontal Circuits That Represent Aversive Experience. Biol Psychiatry. 2016 May 1. PMID: 27079495
- Opler LA, Opler MG, Arnsten AF: Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish. CNS Spectr. 2016 Feb; 2015 Jan 26. PMID: 25619798
- Arnsten AF, Wang M: Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders. Annu Rev Pharmacol Toxicol. 2016. PMID: 26738476
- Gamo NJ, Lur G, Higley MJ, Wang M, Paspalas CD, Vijayraghavan S, Yang Y, Ramos BP, Peng K, Kata A, Boven L, Lin F, Roman L, Lee D, Arnsten AF: Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. Biol Psychiatry. 2015 Dec 15; 2015 Feb 4. PMID: 25731884
- Wang M, Arnsten AF: Physiological approaches to understanding molecular actions on dorsolateral prefrontal cortical neurons underlying higher cognitive processing. Dongwuxue Yanjiu. 2015 Nov 18. PMID: 26646567
- Arnsten AF: Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci. 2015 Oct; 2015 Sep 25. PMID: 26404712
- Arnsten AF, Wang M, Paspalas CD: Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders. Pharmacol Rev. 2015 Jul. PMID: 26106146
- Connor DF, Ford JD, Arnsten AF, Greene CA: An Update on Posttraumatic Stress Disorder in Children and Adolescents. Clin Pediatr (Phila). 2015 Jun; 2014 Jul 2. PMID: 24990362
- Wang M, Arnsten AF: Contribution of NMDA receptors to dorsolateral prefrontal cortical networks in primates. Neurosci Bull. 2015 Apr; 2015 Mar 9. PMID: 25754145
- McKee SA, Potenza MN, Kober H, Sofuoglu M, Arnsten AF, Picciotto MR, Weinberger AH, Ashare R, Sinha R: A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J Psychopharmacol. 2015 Mar; 2014 Dec 16. PMID: 25516371
- Hains AB, Yabe Y, Arnsten AF: Chronic Stimulation of Alpha-2A-Adrenoceptors With Guanfacine Protects Rodent Prefrontal Cortex Dendritic Spines and Cognition From the Effects of Chronic Stress. Neurobiol Stress. 2015. PMID: 25664335
- Arnsten AF, Raskind MA, Taylor FB, Connor DF: The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder. Neurobiol Stress. 2015 Jan 1. PMID: 25436222
- El-Hassar L, Simen AA, Duque A, Patel KD, Kaczmarek LK, Arnsten AF, Yeckel MF: Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels. Biol Psychiatry. 2014 Sep 15; 2014 Jan 20. PMID: 24560582
- 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. Proc Natl Acad Sci U S A. 2014 Apr 1; 2014 Mar 18. PMID: 24707050
- Arnsten AF, Jin LE: Molecular influences on working memory circuits in dorsolateral prefrontal cortex. Prog Mol Biol Transl Sci. 2014. PMID: 24484703
- Arnsten AF: The neurobiology of thought: the groundbreaking discoveries of Patricia Goldman-Rakic 1937-2003. Cereb Cortex. 2013 Oct; 2013 Aug 7. PMID: 23926115
- Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M: Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci U S A. 2013 Jul 16; 2013 Jul 1. PMID: 23818597
- Paspalas CD, Wang M, Arnsten AF: Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia. Cereb Cortex. 2013 Jul; 2012 Jun 12. PMID: 22693343
- 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 Feb 20. PMID: 23439125
- Caetano MS, Jin LE, Harenberg L, Stachenfeld KL, Arnsten AF, Laubach M: Noradrenergic control of error perseveration in medial prefrontal cortex. Front Integr Neurosci. 2012; 2013 Jan 2. PMID: 23293590
- Arnsten AF, Wang MJ, Paspalas CD: Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron. 2012 Oct 4. PMID: 23040817
- Arnsten AF, Rubia K: Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry. 2012 Apr; 2012 Mar 3. PMID: 22449642
- Caetano MS, Horst NK, Harenberg L, Liu B, Arnsten AF, Laubach M: Lost in transition: aging-related changes in executive control by the medial prefrontal cortex. J Neurosci. 2012 Mar 14. PMID: 22423097
- Arnsten AF, Jin LE: Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012 Mar; 2012 Mar 29. PMID: 22461743
- Kim S, Bobeica I, Gamo NJ, Arnsten AF, Lee D: Effects of α-2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology (Berl). 2012 Jan; 2011 Oct 7. PMID: 21979441
- Arnsten AF, Pliszka SR: Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacol Biochem Behav. 2011 Aug; 2011 Feb 2. PMID: 21295057
- Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D, Arnsten AF: Neuronal basis of age-related working memory decline. Nature. 2011 Jul 27; 2011 Jul 27. PMID: 21796118
- Arnsten AF, Casey BJ: Prefrontal cortical organization and function: implications for externalizing disorders. Biol Psychiatry. 2011 Jun 15. PMID: 21640860
- Arnsten AF: Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011 Jun 15; 2011 Apr 13. PMID: 21489408
- Gamo NJ, Arnsten AF: Molecular modulation of prefrontal cortex: rational development of treatments for psychiatric disorders. Behav Neurosci. 2011 Jun. PMID: 21480691
- Arnsten AF: Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. Int J Dev Neurosci. 2011 May; 2011 Feb 21. PMID: 21345366
- Arnsten AF: The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother. 2010 Oct. PMID: 20925474
- Gamo NJ, Wang M, Arnsten AF: Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 2010 Oct; 2010 Sep 1. PMID: 20855046
- Arnsten AF, Paspalas CD, Gamo NJ, Yang Y, Wang M: Dynamic Network Connectivity: A new form of neuroplasticity. Trends Cogn Sci. 2010 Aug; 2010 Jun 16. PMID: 20554470
- Hains AB, Vu MA, Maciejewski PK, van Dyck CH, Gottron M, Arnsten AF: Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc Natl Acad Sci U S A. 2009 Oct 20; 2009 Sep 11. PMID: 19805148
- Arnsten AF: Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009 Jun. PMID: 19455173
- Arnsten AF: The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex. J Pediatr. 2009 May 1. PMID: 20596295
- Brennan AR, Yuan P, Dickstein DL, Rocher AB, Hof PR, Manji H, Arnsten AF: Protein kinase C activity is associated with prefrontal cortical decline in aging. Neurobiol Aging. 2009 May; 2007 Oct 4. PMID: 17919783
- Arnsten AF: Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 2009. PMID: 19621976
- Simen AA, DiLeone R, Arnsten AF: Primate models of schizophrenia: future possibilities. Prog Brain Res. 2009; 2009 Nov 20. PMID: 20302824
- Budel S, Padukkavidana T, Liu BP, Feng Z, Hu F, Johnson S, Lauren J, Park JH, McGee AW, Liao J, Stillman A, Kim JE, Yang BZ, Sodi S, Gelernter J, Zhao H, Hisama F, Arnsten AF, Strittmatter SM: Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J Neurosci. 2008 Dec 3. PMID: 19052207
- Hains AB, Arnsten AF: Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. Learn Mem. 2008 Aug; 2008 Aug 6. PMID: 18685145
- van Dyck CH, Avery RA, MacAvoy MG, Marek KL, Quinlan DM, Baldwin RM, Seibyl JP, Innis RB, Arnsten AF: Striatal dopamine transporters correlate with simple reaction time in elderly subjects. Neurobiol Aging. 2008 Aug; 2007 Mar 23. PMID: 17363113
- Ramos BP, Colgan LA, Nou E, Arnsten AF: Beta2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals. Neurobiol Aging. 2008 Jul; 2007 Mar 23. PMID: 17363115
- Brennan AR, Dolinsky B, Vu MA, Stanley M, Yeckel MF, Arnsten AF: Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory. Learn Mem. 2008 Mar; 2008 Feb 19. PMID: 18285467
- Brennan AR, Arnsten AF: Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function. Ann N Y Acad Sci. 2008. PMID: 18591484
- Arnsten AF: Catecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness. Cereb Cortex. 2007 Sep; 2007 Apr 13. PMID: 17434919
- 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: Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007 Apr 20. PMID: 17448997
- Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF: Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007 Mar; 2007 Feb 4. PMID: 17277774
- Ramos BP, Arnsten AF: Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007 Mar; 2006 Dec 28. PMID: 17303246
- Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AF: Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem. 2006 Nov-Dec; 2006 Nov 13. PMID: 17101879
- Arnsten AF: Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology. 2006 Nov; 2006 Jul 19. PMID: 16855530
- Shansky RM, Rubinow K, Brennan A, Arnsten AF: The effects of sex and hormonal status on restraint-stress-induced working memory impairment. Behav Brain Funct. 2006 Mar 7; 2006 Mar 7. PMID: 16522198
- Arnsten AF: Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry. 2006. PMID: 16961424
- Ramos BP, Colgan L, Nou E, Ovadia S, Wilson SR, Arnsten AF: The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys. Biol Psychiatry. 2005 Dec 1; 2005 Jul 25. PMID: 16043136
- Arnsten AF, Li BM: Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005 Jun 1. PMID: 15950011
- Arnsten AF, Ramos BP, Birnbaum SG, Taylor JR: Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. Trends Mol Med. 2005 Mar. PMID: 15760770
- Arnsten AF, Shansky RM: Adolescence: vulnerable period for stress-induced prefrontal cortical function? Introduction to part IV. Ann N Y Acad Sci. 2004 Jun. PMID: 15251883
- Arnsten AF: Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berl). 2004 Jun; 2003 Dec 19. PMID: 15205875
- Ramos BP, Birnbaum SG, Lindenmayer I, Newton SS, Duman RS, Arnsten AF: Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron. 2003 Nov 13. PMID: 14622586
- Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF: Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci. 2002 Oct 1. PMID: 12351753
- Franowicz JS, Arnsten AF: Actions of alpha-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype. Psychopharmacology (Berl). 2002 Jul; 2002 Jun 13. PMID: 12122489