Medications to treat cognitive disorders are increasingly needed, yet researchers have had few successes in this challenging arena. Cognitive abilities in primates arise from highly evolved -methyl--aspartate (NMDA) receptor circuits in layer III of the dorsolateral prefrontal cortex. These circuits have unique modulatory needs that can differ from the layer V neurons that predominate in rodents, but they offer multiple therapeutic targets. Cognitive improvement often requires low doses that enhance the pattern of information held in working memory, whereas higher doses can produce nonspecific changes that obscure information. Identifying appropriate doses for clinical trials may be helped by assessments in monkeys and by flexible, individualized dose designs. The use of guanfacine (Intuniv) for prefrontal cortical disorders was based on research in monkeys, supporting this approach. Coupling our knowledge of higher primate circuits with the powerful methods now available in drug design will help create effective treatments for cognitive disorders.


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Literature Cited

  1. Lewis DA, Campbell MJ, Terry RD, Morrison JH. 1.  1987. Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J. Neurosci. 7:1799–808 [Google Scholar]
  2. Bussière T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR. 2.  2003. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: stereologic analysis of prefrontal cortex area 9. J. Comp. Neurol. 463:281–302 [Google Scholar]
  3. Lewis DA, Gonzalez-Burgos GR. 3.  2006. Pathophysiologically based treatment interventions in schizophrenia. Nat. Med. 12:1016–22 [Google Scholar]
  4. Arion D, Corradi JP, Tang S, Datta D, Boothe F. 4.  et al. 2015. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol. Psychiatry. 201397–405 [Google Scholar]
  5. Arnsten AFT, Wang M, Paspalas CD. 5.  2012. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76:223–39 [Google Scholar]
  6. Preuss T. 6.  1995. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered. J. Cogn. Neurosci. 7:1–24 [Google Scholar]
  7. Fuster JM. 7.  2008. The Prefrontal Cortex San Diego, CA: Academic [Google Scholar]
  8. Arnsten AFT. 8.  2013. The neurobiology of thought: the groundbreaking discoveries of Patricia Goldman-Rakic 1937–2003. Cereb. Cortex 23:2269–81 [Google Scholar]
  9. Robbins TW. 9.  1996. Dissociating executive functions of the prefrontal cortex. Phil. Trans. R. Soc. Lond. 351:1463–71 [Google Scholar]
  10. Stuss DT, Knight RT. 10.  2002. Principles of Frontal Lobe Function New York: Oxford Univ. Press [Google Scholar]
  11. Thompson-Schill SL, Jonides J, Marshuetz C, Smith EE, D'Esposito M. 11.  et al. 2002. Effects of frontal lobe damage on interference effects in working memory. Cogn. Affect. Behav. Neurosci. 2:109–20 [Google Scholar]
  12. Goldman-Rakic PS. 12.  1987. Circuitry of the primate prefrontal cortex and the regulation of behavior by representational memory. Handbook of Physiology, The Nervous System, Higher Functions of the Brain F Plum 373–417 Bethesda, MD: Am. Physiol. Soc. [Google Scholar]
  13. Ongür D, Price JL. 13.  2000. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10:206–19 [Google Scholar]
  14. Funahashi S, Bruce CJ, Goldman-Rakic PS. 14.  1989. Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J. Neurophysiol. 61:331–49 [Google Scholar]
  15. Seo H, Lee D. 15.  2009. Behavioral and neural changes after gains and losses of conditioned reinforcers. J. Neurosci. 29:3627–41 [Google Scholar]
  16. Badre D, D'Esposito M. 16.  2007. Functional magnetic resonance imaging evidence for a hierarchical organization of the prefrontal cortex. J. Cogn. Neurosci. 19:2082–99 [Google Scholar]
  17. Hilgenstock R, Weiss T, Witte OW. 17.  2014. You'd better think twice: post-decision perceptual confidence. NeuroImage 99:323–31 [Google Scholar]
  18. Fleming SM, Huijgen J, Dolan RJ. 18.  2012. Prefrontal contributions to metacognition in perceptual decision making. J. Neurosci. 32:6117–25 [Google Scholar]
  19. Amodio DM, Frith CD. 19.  2006. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7:268–77 [Google Scholar]
  20. Seo H, Cai X, Donahue CH, Lee D. 20.  2014. Neural correlates of strategic reasoning during competitive games. Science 346:340–43 [Google Scholar]
  21. Robinson RG, Lipsey JR. 21.  1985. Cerebral localization of emotion based on clinical-neuropathological correlations: methodological issues. Psychiatr. Dev. 3:335–47 [Google Scholar]
  22. Aron AR. 22.  2011. From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses. Biol. Psychiatry 69:e55–68 [Google Scholar]
  23. Drevets WC, Price JL, Simpson JRJ, Todd RD, Reich T. 23.  et al. 1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824–27 [Google Scholar]
  24. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D. 24.  et al. 2005. Deep brain stimulation for treatment-resistant depression. Neuron 45:651–60 [Google Scholar]
  25. Insel TR, Winslow JT. 25.  1992. Neurobiology of obsessive compulsive disorder. Psychiatr. Clin. N. Am. 15:813–24 [Google Scholar]
  26. Shaw P, Lalonde FM, Lepage C, Rabin C, Eckstrand K. 26.  et al. 2009. Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder. Arch. Gen. Psychiatry 66:888–96 [Google Scholar]
  27. Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J. 27.  et al. 1999. Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder. Am. J. Psychiatry 156:1986–88 [Google Scholar]
  28. Sugranyes G, Kyriakopoulos M, Corrigall R, Taylor E, Frangou S. 28.  2011. Autism spectrum disorders and schizophrenia: meta-analysis of the neural correlates of social cognition. PLOS ONE 6:e25322 [Google Scholar]
  29. Kritzer MF, Goldman-Rakic PS. 29.  1995. Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the rhesus monkey. J. Comp. Neurol. 359:131–43 [Google Scholar]
  30. Elston GN. 30.  2000. Pyramidal cells of the frontal lobe: all the more spinous to think with. J. Neurosci. 20:RC95 [Google Scholar]
  31. Elston GN. 31.  2003. Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function. Cereb. Cortex 13:1124–38 [Google Scholar]
  32. Elston GN, Benavides-Piccione R, Elston A, Zietsch B, Defelipe J. 32.  et al. 2006. Specializations of the granular prefrontal cortex of primates: implications for cognitive processing. Anat. Rec. Part A Discov. Mol. Cell Evol. Biol. 288:26–35 [Google Scholar]
  33. DeFelipe J. 33.  2011. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity. Front. Neuroanat. 5:29 [Google Scholar]
  34. Amatrudo JM, Weaver CM, Crimins JL, Hof PR, Rosene DL, Luebke JI. 34.  2012. Influence of highly distinctive structural properties on the excitability of pyramidal neurons in monkey visual and prefrontal cortices. J. Neurosci. 32:13644–60 [Google Scholar]
  35. Young ME, Ohm DT, Dumitriu D, Rapp PR, Morrison JH. 35.  2014. Differential effects of aging on dendritic spines in visual cortex and prefrontal cortex of the rhesus monkey. Neuroscience 274:33–43 [Google Scholar]
  36. Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE. 36.  et al. 2014. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. PNAS 111:5036–41 [Google Scholar]
  37. Bourne J, Harris KM. 37.  2007. Do thin spines learn to be mushroom spines that remember?. Curr. Opin. Neurobiol. 17:381–86 [Google Scholar]
  38. Goldman-Rakic PS. 38.  1995. Cellular basis of working memory. Neuron 14:477–85 [Google Scholar]
  39. Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE. 39.  et al. 2013. NMDA receptors subserve working memory persistent neuronal firing in dorsolateral prefrontal cortex. Neuron 77:736–49 [Google Scholar]
  40. Liu XB, Murray KD, Jones EG. 40.  2004. Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development. J. Neurosci. 24:8885–95 [Google Scholar]
  41. Gabernet L, Jadhav SP, Feldman DE, Carandini M, Scanziani M. 41.  2005. Somatosensory integration controlled by dynamic thalamocortical feed-forward inhibition. Neuron 48:315–27 [Google Scholar]
  42. Funahashi S, Bruce CJ, Goldman-Rakic PS. 42.  1991. Neuronal activity related to saccadic eye movements in the monkey's dorsolateral prefrontal cortex. J. Neurophysiol. 65:1464–83 [Google Scholar]
  43. Ford JM, Mathalon DH, Whitfield S, Faustman WO, Roth WT. 43.  2002. Reduced communication between frontal and temporal lobes during talking in schizophrenia. Biol. Psychiatry 51:485–92 [Google Scholar]
  44. Caetano MS, Horst NK, Harenberg L, Liu B, Arnsten AFT, Laubach L. 44.  2012. Lost in transition: aging-related changes in executive control by the medial prefrontal cortex. J. Neurosci. 32:3765–77 [Google Scholar]
  45. Selemon LD, Rajkowska G, Goldman-Rakic PS. 45.  1995. Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch. Gen. Psychiatry 52:805–18 [Google Scholar]
  46. Selemon LD, Goldman-Rakic PS. 46.  1999. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45:17–25 [Google Scholar]
  47. Glantz LA, Lewis DA. 47.  2000. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57:65–73 [Google Scholar]
  48. Black JE, Kodish IM, Grossman AW, Klintsova AY, Orlovskaya D. 48.  et al. 2004. Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia. Am. J. Psychiatry 161:742–44 [Google Scholar]
  49. Curley AA, Eggan SM, Lazarus MS, Huang ZJ, Volk DW, Lewis DA. 49.  2013. Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia. Neurobiol. Dis. 50:179–86 [Google Scholar]
  50. Pearson RCA, Esiri MM, Hiorns RW, Wilcock GK, Powell TPS. 50.  1985. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. PNAS 82:4531–34 [Google Scholar]
  51. Braak H, Braak E. 51.  1995. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol. Aging 16:271–78 [Google Scholar]
  52. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. 52.  2011. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70:960–69 [Google Scholar]
  53. Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AFT, Wang M. 53.  2013. Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. PNAS 110:12078–83 [Google Scholar]
  54. Arnsten AFT, Paspalas CD, Gamo NJ, Yang Y, Wang M. 54.  2010. Dynamic Network Connectivity: a new form of neuroplasticity. Trends Cog. Sci. 14:365–75 [Google Scholar]
  55. Hobson JA. 55.  1992. Sleep and dreaming: induction and mediation of REM sleep by cholinergic mechanisms. Curr. Opin. Neurobiol. 2:759–63 [Google Scholar]
  56. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. 56.  1997. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88:615–26 [Google Scholar]
  57. Hongpaisan J, Alkon DL. 57.  2007. A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC. PNAS 104:19571–76 [Google Scholar]
  58. Nagy G, Reim K, Matti U, Brose N, Binz T. 58.  et al. 2004. Regulation of releasable vesicle pool sizes by protein kinase A-dependent phosphorylation of SNAP-25. Neuron 41:417–29 [Google Scholar]
  59. Chen S, Wang J, Siegelbaum SA. 59.  2001. Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol. 117:491–504 [Google Scholar]
  60. Jentsch TJ. 60.  2000. Neuronal KCNQ potassium channels: physiology and role in disease. Nat. Rev. Neurosci. 1:21–30 [Google Scholar]
  61. Paspalas CD, Wang M, Arnsten AFT. 61.  2013. 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 23:1643–54 [Google Scholar]
  62. Muly EC, Maddox M, Smith Y. 62.  2003. Distribution of mGluR1 α and mGluR5 immunolabeling in primate prefrontal cortex. J. Comp. Neurol. 467:521–35 [Google Scholar]
  63. Arnsten AFT, Wang M, Paspalas CD. 63.  2015. Dopamine's actions in primate prefrontal cortex: challenges for treating cognitive disorders. Pharmacol. Rev. 67:681–96 [Google Scholar]
  64. Vijayraghavan S, Wang M, Birnbaum SG, Bruce CJ, Williams GV, Arnsten AFT. 64.  2007. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat. Neurosci. 10:376–84 [Google Scholar]
  65. Gamo NJ, Lur G, Higley MJ, Wang M, Paspalas CD. 65.  et al. 2015. Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels. Biol. Psychiatry. 78860–70 [Google Scholar]
  66. Birnbaum SB, Yuan P, Wang M, Vijayraghavan S, Bloom A. 66.  et al. 2004. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306:882–84 [Google Scholar]
  67. Wang M, Vijayraghavan S, Goldman-Rakic PS. 67.  2004. Selective D2 receptor actions on the functional circuitry of working memory. Science 303:853–56 [Google Scholar]
  68. Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E. 68.  2007. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol. Pharmacol. 72:477–84 [Google Scholar]
  69. Huang CC, Hsu KS. 69.  2006. Presynaptic mechanism underlying cAMP-induced synaptic potentiation in medial prefrontal cortex pyramidal neurons. Mol. Pharmacol. 69:846–56 [Google Scholar]
  70. Defelipe J. 70.  2011. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity. Front. Neuroanat. 5:29 [Google Scholar]
  71. U'Prichard DC, Bechtel WD, Rouot BM, Snyder SH. 71.  1979. Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. Mol. Pharmacol. 16:47–60 [Google Scholar]
  72. Arnsten AFT, Li B-M. 72.  2005. Neurobiology of executive functions: catecholamine influences on prefrontal cortical function. Biol. Psychiatry 57:1377–84 [Google Scholar]
  73. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A. 73.  et al. 2007. α2A-adrenoceptor stimulation strengthens working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410 [Google Scholar]
  74. Li B-M, Mao Z-M, Wang M, Mei Z-T. 74.  1999. Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys. Neuropsychopharmacology 21:601–10 [Google Scholar]
  75. Mao Z-M, Arnsten AFT, Li B-M. 75.  1999. Local infusion of α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol. Psychiatry 46:1259–65 [Google Scholar]
  76. Arnsten AFT. 76.  2010. The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev. Neurother. 10:1595–605 [Google Scholar]
  77. Kim S, Bobeica I, Gamo NJ, Arnsten AFT, Lee D. 77.  2012. Effects of α-2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology 219:363–75 [Google Scholar]
  78. Li B-M, Mei Z-T. 78.  1994. Delayed response deficit induced by local injection of the α2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav. Neural. Biol. 62:134–39 [Google Scholar]
  79. Ma C-L, Qi X-L, Peng J-Y, Li B-M. 79.  2003. Selective deficit in no-go performance induced by blockade of prefrontal cortical α2-adrenoceptors in monkeys. NeuroReport 14:1013–16 [Google Scholar]
  80. Ma C-L, Arnsten AFT, Li B-M. 80.  2005. Locomotor hyperactivity induced by blockade of prefrontal cortical α2-adrenoceptors in monkeys. Biol. Psychiatry 57:192–95 [Google Scholar]
  81. Zhang Z, Cordeiro Matos S, Jego S, Adamantidis A, Séguéla P. 81.  2013. Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors. PLOS ONE 8:e66122 [Google Scholar]
  82. Kamisaki Y, Hamahashi T, Hamada T, Maeda K, Itoh T. 82.  1992. Presynaptic inhibition by clonidine of neurotransmitter amino acid release in various brain regions. Eur. J. Pharmacol. 217:57–63 [Google Scholar]
  83. Yi F, Liu S-S, Luo F, Zhang X-H, Li B-M. 83.  2013. Signaling mechanism underlying α2A-adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats. Eur. J. Neurosci. 38:2364–73 [Google Scholar]
  84. Franowicz JS, Kessler L, Dailey Borja CM, Kobilka BK, Limbird LE, Arnsten AFT. 84.  2002. Mutation of the α2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J. Neurosci. 22:8771–77 [Google Scholar]
  85. Kauser H, Sahu S, Kumar S, Panjwani U. 85.  2013. Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline. Neuroscience 254:110–19 [Google Scholar]
  86. Hains AB, Yabe Y, Arnsten AFT. 86.  2015. Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Neurobiol. Stress 2:1–9 [Google Scholar]
  87. Ren W-W, Liu Y, Li B-M. 87.  2011. Stimulation of α2A-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol. Cell Neurosci. 49:205–16 [Google Scholar]
  88. Gyoneva S, Traynelis SF. 88.  2013. Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors. J. Biol. Chem. 288:15291–302 [Google Scholar]
  89. Biederman J, Melmed RD, Patel A, McBurnett K, Konow J. 89.  et al. 2008. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 121:e73–84 [Google Scholar]
  90. Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L. 90.  et al. 2001. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am. J. Psychiatry 158:1067–74 [Google Scholar]
  91. McCracken JT, Aman MG, McDougle CJ, Tierney E, Shiraga S. 91.  et al. 2010. Possible influence of variant of the P-glycoprotein gene (MDR1/ABCB1) on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity. J. Child Adolesc. Psychopharmacol. 20:1–5 [Google Scholar]
  92. Connor DF, Grasso DJ, Slivinsky MD, Pearson GS, Banga A. 92.  2013. An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents. J. Child Adolesc. Psychopharmacol. 23:244–51 [Google Scholar]
  93. Arnsten AFT, Raskind M, Taylor FB, Connor DF. 93.  2015. The effects of stress exposure on prefrontal cortex: translating basic research into successful treatments for post-traumatic stress disorder. Neurobiol. Stress 1:89–99 [Google Scholar]
  94. McAllister TW, McDonald BC, Flashman LA, Ferrell RB, Tosteson TD. 94.  et al. 2011. Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: altered working memory and BOLD response. Int. J. Psychophysiol. 82:107–14 [Google Scholar]
  95. Fox HC, Seo D, Tuit K, Hansen J, Kimmerling A. 95.  et al. 2012. Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings. J. Psychopharmacol. 26:958–72 [Google Scholar]
  96. McKee SA, Potenza MN, Kober H, Sofouglu M, Arnsten AFT. 96.  et al. 2015. A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J. Psychopharmacol 29:300–11 [Google Scholar]
  97. Cannon TD, Chung Y, He G, Sun D, Jacobson A. 97.  et al. 2014. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry 77:147–57 [Google Scholar]
  98. Arnsten AFT, Cai JX, Goldman-Rakic PS. 98.  1988. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J. Neurosci. 8:4287–98 [Google Scholar]
  99. Franowicz JCS, Arnsten AFT. 99.  1998. The α-2A noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136:8–14 [Google Scholar]
  100. Arnsten AFT, Steere JC, Hunt RD. 100.  1996. The contribution of α2-noradrenergic mechanisms to prefrontal cortical cognitive function: potential significance to attention deficit hyperactivity disorder. Arch. Gen. Psychiatry 53:448–55 [Google Scholar]
  101. Chappell PB, Riddle MA, Scahill L, Lynch KA, Schultz R. 101.  et al. 1995. Guanfacine treatment of comorbid attention deficit hyperactivity disorder and Tourette's syndrome: preliminary clinical experience. J. Am. Acad. Child. Adolesc. Psychiatry 34:1140–46 [Google Scholar]
  102. Hunt RD, Arnsten AFT, Asbell MD. 102.  1995. An open trial of guanfacine in the treatment of attention deficit hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 34:50–54 [Google Scholar]
  103. Martin LF, Freedman R. 103.  2007. Schizophrenia and the α7 nicotinic acetylcholine receptor. Int. Rev. Neurobiol. 78:225–46 [Google Scholar]
  104. Wilens TE, Decker MW. 104.  2007. Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition. Biochem. Pharmacol. 74:1212–23 [Google Scholar]
  105. Levin ED. 105.  2012. α7-Nicotinic receptors and cognition. Curr. Drug Targets. 13:602–6 [Google Scholar]
  106. Kristiansen LV, Bakir B, Haroutunian V, Meador-Woodruff JH. 106.  2010. Expression of the NR2B-NMDA receptor trafficking complex in prefrontal cortex from a group of elderly patients with schizophrenia. Schizophr. Res. 119:198–209 [Google Scholar]
  107. Kristiansen LV, Patel SA, Haroutunian VH, Meador-Woodruff JH. 107.  2010. Expression of the NR2B-NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia. Synapse 64:495–502 [Google Scholar]
  108. Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM. 108.  et al. 2012. Molecular evidence of N-methyl-d-aspartate receptor hypofunction in schizophrenia. Mol. Psychiatry 18:1185–92 [Google Scholar]
  109. Mexal S, Berger R, Logel J, Ross RG, Freedman R, Leonard S. 109.  2010. Differential regulation of α7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. J. Mol. Neurosci. 40:185–95 [Google Scholar]
  110. Ahlers E, Hahn E, Ta TM, Goudarzi E, Dettling M, Neuhaus AH. 110.  2014. Smoking improves divided attention in schizophrenia. Psychopharmacology 231:3871–77 [Google Scholar]
  111. Hajós M, Rogers BN. 111.  2010. Targeting α7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr. Pharm. Des. 16:538–54 [Google Scholar]
  112. Williams DK, Wang J, Papke RL. 112.  2011. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations. Biochem. Pharmacol. 82:915–30 [Google Scholar]
  113. Snyder EM, Nong Y, Almeida CG, Paul S, Moran TH. 113.  et al. 2005. Regulation of NMDA receptor trafficking by amyloid-β. Nat. Neurosci. 8:1051–58 [Google Scholar]
  114. Mrzljak L, Levey AI, Goldman-Rakic PS. 114.  1993. Association of m1 and m2 muscarinic receptor proteins with asymmetric synapses in the primate cerebral cortex: morphological evidence for cholinergic modulation of excitatory neurotransmission. PNAS 90:5194–98 [Google Scholar]
  115. Davie BJ, Christopoulos A, Scammells PJ. 115.  2013. Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. ACS Chem. Neurosci. 4:1026–48 [Google Scholar]
  116. Engberg G, Eriksson E. 116.  1991. Effects of α2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn-Schmiedeberg's Arch. Pharmacol. 343:472–77 [Google Scholar]
  117. Manji HK, Lenox RH. 117.  1999. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol. Psychiatry 46:1328–51 [Google Scholar]
  118. Zarate CAJ, Singh JB, Carlson PJ, Quiroz JA, Jolkovsky L. 118.  et al. 2007. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar. Disorders 9:561–70 [Google Scholar]
  119. Birnbaum SG, Gobeske KT, Auerbach J, Taylor JR, Arnsten AFT. 119.  1999. A role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in prefrontal cortex. Biol. Psychiatry 46:1266–74 [Google Scholar]
  120. Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A. 120.  et al. 2003. Reduction in nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am. J. Psychiatry 160:371–73 [Google Scholar]
  121. Taylor FB, Lowe K, Thompson C, McFall MM, Peskind ER. 121.  et al. 2006. Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. Biol. Psychiatry 59:577–81 [Google Scholar]
  122. Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC. 122.  2007. Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific. Cereb. Cortex 17:18–27 [Google Scholar]
  123. Walker SC, Robbins TW, Roberts AC. 123.  2009. Differential contributions of dopamine and serotonin to orbitofrontal cortex function in the marmoset. Cereb. Cortex 19:889–98 [Google Scholar]
  124. Puig MV, Miller EK. 124.  2012. The role of prefrontal dopamine D1 receptors in the neural mechanisms of associative learning. Neuron 74:874–86 [Google Scholar]
  125. Puig MV, Miller EK. 125.  2015. Neural substrates of dopamine D2 receptor modulated executive functions in the monkey prefrontal cortex. Cereb. Cortex. 252980–87 [Google Scholar]
  126. Noudoost B, Moore T. 126.  2011. Control of visual cortical signals by prefrontal dopamine. Nature 474:372–75 [Google Scholar]
  127. Opler LA, Opler MGA, Arnsten AFT. 127.  2015. Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish. CNS Spectr. In press. doi: 10.1017/S1092852914000686 [Google Scholar]
  128. Cannon TD, Thompson PM, van Erp TG, Toga AW, Poutanen VP. 128.  et al. 2002. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. PNAS 99:3228–33 [Google Scholar]
  129. Calabrese B, Halpain S. 129.  2005. Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron 48:77–90 [Google Scholar]
  130. Hains AB, Vu MAT, Maciejewski PK, van Dyck CH, Gottron M, Arnsten AFT. 130.  2009. Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. PNAS 106:17957–62 [Google Scholar]
  131. Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V. 131.  et al. 2014. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat. Med. 20:531–35 [Google Scholar]
  132. Yanagawa Y, Hiraide S, Matsumoto M, Togashi H. 132.  2014. Rapid induction of REDD1 gene expression in macrophages in response to stress-related catecholamines. Immunol. Lett. 158:109–15 [Google Scholar]
  133. Bachmann VA, Riml A, Huber RG, Baillie GS, Liedl KR. 133.  et al. 2013. Reciprocal regulation of PKA and Rac signaling. PNAS 110:8531–36 [Google Scholar]
  134. Hayashi-Takagi A, Araki Y, Nakamura M, Vollrath B, Duron SG. 134.  et al. 2014. PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence. PNAS 111:6461–66 [Google Scholar]
  135. Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H. 135.  et al. 2010. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat. Neurosci. 13:327–32 [Google Scholar]
  136. MacKenzie KF, Wallace DA, Hill EV, Anthony DF, Henderson DJP. 136.  et al. 2011. Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. Biochem. J. 435:755–69 [Google Scholar]

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