Psychopharmacology

, Volume 174, Issue 1, pp 25–31

Adrenergic targets for the treatment of cognitive deficits in schizophrenia

Review

Abstract

Rationale

The cognitive functions of the prefrontal cortex (PFC) are profoundly impaired in schizophrenic patients. Although dopamine has been the major focus of schizophrenia research, norepinephrine (NE) also has marked influences on PFC cognitive functioning.

Objective

This review aims to identify the adrenergic receptors which may be appropriate targets for therapeutic actions in schizophrenia.

Methods

Studies of adrenergic mechanisms influencing PFC function in animals and humans were reviewed.

Results

Modest levels of NE engage postsynaptic α2A-adrenergic receptors and strengthen working memory. These beneficial effects have been observed at both the behavioral and cellular levels in animals, and have translated to the clinic in patients with PFC impairments. Thus, the α2A-adrenergic receptor is a proven molecular target. In contrast, high levels of NE released during stress impair PFC cognitive function via activation of protein kinase C intracellular signaling, a pathway increasingly associated with the etiology of schizophrenia. Blockade of α1 adrenoceptors or inhibition of protein kinase C helps to protect PFC cognitive function in animals, and may have similar therapeutic actions in humans. Blockade of the α2C receptor may also be helpful in enhancing catecholamine release while blocking detrimental DA actions in striatum.

Conclusion

Highly selective adrenergic agents may be useful for enhancing PFC function in schizophrenic patients

Keywords

Schizophrenia Cognitive deficit Prefrontal cortex Norepinephrine Adrenergic receptors 

References

  1. Aoki C, Go C-G, Venkatesan C, Kurose H (1994) Perikaryal and synaptic localization of alpha2A-adrenergic receptor-like immunoreactivity. Brain Res 650:181–204CrossRefPubMedGoogle Scholar
  2. Aoki C, Venkatesan C, Go C-G, Forman R, Kurose H (1998) Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex 8:269–277CrossRefPubMedGoogle Scholar
  3. Arnsten AFT (1997) Catecholamine regulation of the prefrontal cortex. J Psychopharmacol 11:151–162Google Scholar
  4. Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cognit Sci 2:436–447CrossRefGoogle Scholar
  5. Arnsten AFT, Cai JX (1993) Postsynaptic alpha-2 receptor stimulation improves working memory in aged monkeys: indirect effects of yohimbine vs. direct effects of clonidine. Neurobiol Aging 14:597–603CrossRefPubMedGoogle Scholar
  6. Arnsten AFT, Contant TA (1992) Alpha-2 adrenergic agonists decrease distractability in aged monkeys performing a delayed response task. Psychopharmacology 108:159–169PubMedGoogle Scholar
  7. Arnsten AFT, Goldman-Rakic PS (1985) Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276PubMedGoogle Scholar
  8. Arnsten AFT, Goldman-Rakic PS (1986) Reversal of stress-induced delayed response deficits in rhesus monkeys by clonidine and naloxone. Soc Neurosci Abstr 12:1464Google Scholar
  9. Arnsten AFT, Goldman-Rakic PS (1998) Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 55:362–369PubMedGoogle Scholar
  10. Arnsten AFT, Robbins TW (2002) Neurochemical modulation of prefrontal cortical function in humans and animals. In: Stuss DT, Knight RT (eds) Principles of frontal lobe function. Oxford University Press, New York, pp 51–84Google Scholar
  11. Arnsten AFT, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects. J Neurosci 8:4287–4298PubMedGoogle Scholar
  12. Arnsten AFT, Steere JC, Hunt RD (1996) The contribution of alpha-2 noradrenergic mechanisms to prefrontal cortical cognitive function: potential significance to attention deficit hyperactivity disorder. Arch Gen Psychiatry 53:448–455Google Scholar
  13. Arnsten AFT, Mathew R, Ubriani R, Taylor JR, Li B-M (1999) Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function. Biol Psychiatry 45:26–31CrossRefPubMedGoogle Scholar
  14. Baldessarini RJ, Huston-Lyons D, Campbell A, Marsh E, Cohen BM (1992) Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry 160:12–16PubMedGoogle Scholar
  15. Birnbaum SG, Gobeske KT, Auerbach J, Taylor JR, Arnsten AFT (1999) A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in prefrontal cortex. Biol Psychiatry 46:1266–1274PubMedGoogle Scholar
  16. Brozoski T, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–931PubMedGoogle Scholar
  17. Cai JX, Arnsten AFT (1997) Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 282:1–7PubMedGoogle Scholar
  18. Cai JX, Ma Y, Xu L, Hu X (1993) Reserpine impairs spatial working memory performance in monkeys: reversal by the alpha-2 adrenergic agonist clonidine. Brain Res 614:191–196PubMedGoogle Scholar
  19. Carlson S, Tanila H, Rama P, Mecke E, Pertovaara A (1992) Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist, on spatial memory performance in adult and aged rats. Behav Neural Biol 58:113–119PubMedGoogle Scholar
  20. Cedarbaum JM, Aghajanian GK (1977) Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol 44:375–385PubMedGoogle Scholar
  21. Cohen BM, Lipinski JF (1986) In vivo potencies of antipsychotic drugs in blocking alpha-1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci 39:2571–2580CrossRefPubMedGoogle Scholar
  22. Coull JT (1994) Pharmacological manipulations of the a-2 noradrenergic system: effects on cognition. Drugs Aging 5:116–126PubMedGoogle Scholar
  23. Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) Contrasting effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology 120:311–321PubMedGoogle Scholar
  24. Coull JT, Frith CD, Dolan RJ, Frackowiak RS, Grasby PM (1997) The neural correlates of the noradrenergic modulation of human attention, arousal and learning. Eur J Neurosci 9:589–598PubMedGoogle Scholar
  25. Darracq L, Blanc G, Glowinski J, Tassin J-P (1998) Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of d-amphetamine. J Neurosci 18:2729–2739PubMedGoogle Scholar
  26. Duman RS, Nestler EJ (1995) Signal transduction pathways for catecholamine receptors. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, N.Y., pp 303–320Google Scholar
  27. Ferry B, Roozendaal B, McGaugh JL (1999) Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between beta- and alpha-1-adrenoceptors. J Neurosci 19:5119–5123PubMedGoogle Scholar
  28. Fields RB, Van Kammen DP, Peters JL, Rosen J, Van Kammen WB, Nugent A, Stipetic M, Linnoila M (1988) Clonidine improves memory function in schizophrenia independently from change in psychosis. Schizophr Res 1:417–423CrossRefPubMedGoogle Scholar
  29. Franowicz JCS, Arnsten AFT (1998) The alpha2A noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136:8–14PubMedGoogle Scholar
  30. Franowicz JS, Kessler L, Dailey-Borja CM, Kobilka BK, Limbird LE, Arnsten AFT (2002) Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci 22:8771–8777PubMedGoogle Scholar
  31. Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L, Parrella M, Davis KL (2001) Guanfacine treatment of cognitive impairment in schizophrenia: a pilot study. Neuropsychopharmacology (in press)Google Scholar
  32. Funahashi S, Bruce CJ, Goldman-Rakic PS (1989) Mnemonic coding of visual space in the monkey’s dorsolateral prefrontal cortex. J Neurophysiol 61:331–349PubMedGoogle Scholar
  33. Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215PubMedGoogle Scholar
  34. Haroutunian V, Kanof PD, Tsuboyama G, Davis KL (1990) Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats. Brain Res 507:261–266CrossRefPubMedGoogle Scholar
  35. Hertel P, Fagerquist MV, Svensson TH (1999) Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade. Science 286:105–107CrossRefPubMedGoogle Scholar
  36. Hunt RD, Mindera RB, Cohen DJ (1985) Clonidine benefits children with attention deficit disorder and hyperactivity: reports of a double-blind placebo-crossover therapeutic trial. J Am Acad Child Psychiatry 24:617–629PubMedGoogle Scholar
  37. Jackson WJ, Buccafusco JJ (1991) Clonidine enhances delayed matching-to-sample performance by young and aged monkeys. Pharmacol Biochem Behav 39:79–84PubMedGoogle Scholar
  38. Jakala P, Riekkinen M, Sirvio J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen PJ (1999a) Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20:460–470PubMedGoogle Scholar
  39. Jakala P, Sirvio J, Riekkinen M, Koivisto E, Kejonen K, Vanhanen M, Riekkinen PJ (1999b) Guanfacine and clonidine, alpha-2 agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology 20:119–130CrossRefPubMedGoogle Scholar
  40. Koh PO, Bergson C, Undie AS, Goldman-Rakic PS, Lidow MS (2003) Up-regulation of the D1 dopamine receptor-interacting protein, calcyon, in patients with schizophrenia. Arch Gen Psychiatry 60:311–319CrossRefPubMedGoogle Scholar
  41. Lezcano N, Mrzljak L, Eubanks S, Levenson R, Goldman-Rakic PS, Bergson C (2000) Dual signaling regulated by calcyon, a D1 dopamine receptor interacting protein. Science 287:1660–1664CrossRefPubMedGoogle Scholar
  42. Li B-M, Mei Z-T (1994) Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol 62:134–139PubMedGoogle Scholar
  43. Li B-M, Mao Z-M, Wang M, Mei Z-T (1999) Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys. Neuropsychopharmacology 21:601–610PubMedGoogle Scholar
  44. Lidow MS (2003) Calcium signaling dysfunction in schizophrenia: a unifying approach. Brain Res Rev (in press)Google Scholar
  45. MacDonald E, Kobilka BK, Scheinin M (1997) Gene targeting—homing in on alpha-2-adrenoceptor subtype function. Trends Pharmacol Sci 18:211–219PubMedGoogle Scholar
  46. Mair RG, McEntree WJ (1986) Cognitive enhancement in Korsakoff’s psychosis by clonidine: a comparison with 1-dopa and ephedrine. Psychopharmacology 88:374–380PubMedGoogle Scholar
  47. Manji HK, Lenox RH (1999) Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 46:1328–1351CrossRefPubMedGoogle Scholar
  48. Manji HK, Lenox RH (2000) Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry 48:518–30CrossRefPubMedGoogle Scholar
  49. Manji HK et al. (2004) Psychopharmacology (in press)Google Scholar
  50. Mao Z-M, Arnsten AFT, Li B-M (1999) Local infusion of alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry 46:1259–1265PubMedGoogle Scholar
  51. Marek GJ, Aghajanian GK (1998) 5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by mu-opiate receptor activation. Neuroscience 86:485–497CrossRefPubMedGoogle Scholar
  52. Marek GJ, Aghajanian GK (1999) 5-HT2A receptor or alpha1-adrenoceptor activation induces EPSCs in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206PubMedGoogle Scholar
  53. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100:6186–6191CrossRefPubMedGoogle Scholar
  54. Mazure CM (1995) Does stress cause psychiatric illness? In: Spiegel D (ed) Progress in psychiatry. American Psychiatric Press, Washington, D.C., p 270Google Scholar
  55. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6:293–301CrossRefPubMedGoogle Scholar
  56. Moffoot A, O’Carroll RE, Murray C, Dougall N, Ebmeier K, Goodwin GM (1994) Clonidine infusion increases uptake of Tc-exametazime in anterior cingulate cortex in Korsakoff’s psychosis. Psychol Med 24:53–61PubMedGoogle Scholar
  57. Murphy BL, Arnsten AFT, Goldman-Rakic PS, Roth RH (1996) Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci USA 93:1325–1329PubMedGoogle Scholar
  58. Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology:106–118Google Scholar
  59. Rama P, Linnankoski I, Tanila H, Pertovaara A, Carlson S (1996) Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys. Pharmacol Biochem Behav 54:1–7CrossRefGoogle Scholar
  60. Riekkinen P, Riekkinen M (1999) THA improves word priming and clonidine enhances fluency and working memory in Alzheimer’s disease. Neuropsychopharmacology 20:357–364CrossRefPubMedGoogle Scholar
  61. Sawaguchi T (1998) Attenuation of delay-period activity of monkey prefrontal cortical neurons by an alpha-2 adrenergic antagonist during an oculomotor delayed-response task. J Neurophysiol 80:2200–2205PubMedGoogle Scholar
  62. Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950PubMedGoogle Scholar
  63. Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, Arnsten AFT, Cohen DJ, Leckman JF (2001) Guanfacine in the treatment of children with tic disorders and ADHD: a placebo-controlled study. Am J Psychiatry 158:1067–1074PubMedGoogle Scholar
  64. Tanila H, Rama P, Carlson S (1996) The effects of prefrontal intracortical microinjections of an alpha-2 agonist, alpha-2 antagonist and lidocaine on the delayed alternation performance of aged rats. Brain Res Bull 40:117–119PubMedGoogle Scholar
  65. Taylor FB, Russo J (2001) Comparing guanfacine and dextroamphetamine for the treatment of adult attention deficit-hyperactivity disorder. J Clin Psychopharmacol 21:223–228CrossRefPubMedGoogle Scholar
  66. van Kammen DP, Kelley M (1991) Dopamine and norepinephrine activity in schizophrenia. An integrative perspective. Schizophr Res 4:173–191CrossRefPubMedGoogle Scholar
  67. Williams GV, Goldman-Rakic PS (1995) Blockade of dopamine D1 receptors enhances memory fields of prefrontal neurons in primate cerebral cortex. Nature 376:572–575PubMedGoogle Scholar
  68. Zahrt J, Taylor JR, Mathew RG, Arnsten AFT (1997) Supranormal stimulation of dopamine D1 receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci 17:8528–8535PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Department of NeurobiologyYale University School of MedicineNew HavenUSA

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