Hostname: page-component-76fb5796d-9pm4c Total loading time: 0 Render date: 2024-04-27T18:07:30.028Z Has data issue: false hasContentIssue false

Role of Norepinephrine in the Pathophysiology of Neuropsychiatric Disorders

Published online by Cambridge University Press:  07 November 2014

Abstract

The concatenation of convergent lines of evidence from basic to clinical research continues to reveal that norepinephrine (NE) is a crucial regulator of a myriad of behaviors ranging from stress response to memory formation. Furthermore, many neuropsychiatric disorders involve neurocircuitry that is directly modulated by NE. This report summarizes the physiological roles of NE, as well as the main findings implicating a role for NE system dysfunction in mood and anxiety disorders, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and Alzheimer's disease. In each of these disorders, there appears to be a complex dysregulation of NE function, with changes in locus ceruleus firing, NE availability, and both pre- and postsynaptic receptor regulation. Many symptoms of these disorders are attributable to abnormalities within distributed neural circuits regulated by NE. Appreciation of NE's role in modulating the neural circuitry mediating cognition and affect should help elucidate the pathophysiology of a variety of neuropsychiatric disorders and the development of novel treatments.

Type
Feature Articles
Copyright
Copyright © Cambridge University Press 2001

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1. Potter, W, Grossman, G, Rudorfer, M. Noradrenergic function in depressive disorders. In: Mann, J, Jupter, D, eds. Biology of Depressive Disorders, Part A: A Systems Perspective. New York, NY: Plenum Press; 1993:127.Google Scholar
2. Schatzberg, A, Schildkraut, J. Recent studies on norepinephrine systems in mood disorders. In: Bloom, F, Kupfer, D, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:911920.Google Scholar
3. Chamey, D. Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry. 1998;59(suppl 14):1114.Google Scholar
4. Ressler, KJ, Nemeroff, CB. The role of serotonergic and noradrenergic systems in depression and anxiety disorders. Depress Anxiety. 2000;12(suppl 1):219.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
5. Southwick, SM, Bremner, JD, Rasmusson, A, Morgan, CA et al. , Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;46:11921204.CrossRefGoogle ScholarPubMed
6. Biederman, J, Spencer, T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Bid Psychiatry. 1999;46:12341242.CrossRefGoogle Scholar
7. Friedman, JI, Adler, DN, Davis, KL. The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. Biol Psychiatry. 1999;46:12431252.CrossRefGoogle Scholar
8. Levitt, P, Rakic, P, Goldman-Rakic, P. Comparative assessment of monoamine afferents in mammalian cerebral cortex. In: Descarries, L, Reader, T, Jasper, H, eds. Monoamine Innervalion of Cerebral Cortex. New York, NY: Alan R Liss; 1984:4160.Google ScholarPubMed
9. Davis, M. Anatomic and physiologic substrates of emotion in an animal model. J Clin Neurophysol. 1998:15:378387.CrossRefGoogle ScholarPubMed
10. Davis, M, Whalen, PJ. The amygdala: vigilance and emotion. Mol Psychiatry. 2001;6:1234.CrossRefGoogle ScholarPubMed
11. Maeda, T, Kojima, Y, Arai, R et al. , Monoaminergic interaction in the central nervous system: a morphological analysis in the locus coeruleus of the rat. Comp Biochem Physiol C. 1991;98:193202.CrossRefGoogle ScholarPubMed
12. Weiner, N, Molinoff, P. Catecholamines. In: Siegel, G, Agranoff, B, Albers, R, Molinoff, P, eds. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. 5th ed. New York, NY: Raven Press; 1984:261281.Google Scholar
13. Foote, S, Aston-Jones, G. Pharmacology and physiology of central noradrenergic systems. In: Bloom, F, Kupfer, D, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:335345.Google Scholar
14. Aston-Jones, G, Chiang, C, Alexinsky, T. Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance. Prog Brain Res. 1991;88:501520.CrossRefGoogle ScholarPubMed
15. Van Bockstaele, E, Peoples, J, Valentino, R. Anatomic basis for differential regulation of the rostrolateral peri-locus coeruleus region by limbic afferents. Biol Psychiatry. 1999;46:13521363.CrossRefGoogle ScholarPubMed
16. Arborelius, L, Owens, M, Plotsky, P, Nemeroff, C. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1990;160:112.CrossRefGoogle Scholar
17. Valentino, R, Aston-Jones, G. Physiological and anatomical determinants of locus coeruleus discharge. In: Bloom, F, Kupfer, D, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:373385.Google Scholar
18. Waterhouse, B, Sessler, F, Cheng, H et al. , New evidence for a gating action of norepinephrine in central neuronal circuits of mammalian brain. Brain Res Bull. 1988;21:425432.CrossRefGoogle ScholarPubMed
19. Mongeau, R, Blier, P, de Montigny, C. The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments. Brain Res Brain Res Rev. 1997;23:145195.CrossRefGoogle ScholarPubMed
20. Cahill, L, McGaugh, J. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci. 1998;21:294299.CrossRefGoogle ScholarPubMed
21. Davis, M. Are different parts of the extended amygdala involved in fear versus anxiety? Biol Psychiatry. 1998;44:12391247.CrossRefGoogle ScholarPubMed
22. Schildkraut, J. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122:509522.CrossRefGoogle ScholarPubMed
23. Potter, W, Muscettola, G, Goodwin, F. Sources of variance in clinical studies in MHPG. In: Maas, J, ed. MHPG: Bask Mechanisms and Psychopathology. New York, NY: Academic Press; 1983:145165.CrossRefGoogle Scholar
24. Roy, A, Jimerson, D, Pickar, D. Plasma MHPG in depressive disorders and relationship to the dexamethasone suppression test. Am J Psychiatry. 1986;126:457469.Google Scholar
25. Sevy, S, Papadimitriou, G, Surmount, D et al. , Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects. Biol Psychiatry. 1989;25:141152.CrossRefGoogle ScholarPubMed
26. Wyatt, R, Portnoy, B, Kupfer, D et al. , Resting plasma catecholamine concentrations in patients with depression and anxiety. Arch Gen Psychiatry. 1971;24:6570.CrossRefGoogle ScholarPubMed
27. Charney, D, Heninger, G, Sternberg, D et al. , Presynaptic adrenergic receptor sensitivity in depression: the effect of long-term desipramine treatment. Arch Gen Psychiatry. 1981;38:13341340.CrossRefGoogle ScholarPubMed
28. Meana, J, Barturen, F, Garcia-Sevilla, J. A2-adrenoceptors. in the brains of suicide victims: increased receptor density associated with major depression. Biol. Psychiatry. 1992;31:471490.CrossRefGoogle Scholar
29. Mann, J, Stanley, M, McBride, P, McEwen, BS. Increased 5-HT2 and B-adrenergic receptor binding in the frontal cortices of suicide victims. Arch Gen Psychiatry. 1986;43:954959.CrossRefGoogle Scholar
30. Matussek, N, Ackenheil, M, Hippius, H et al. , Effects of clonidine on growth hormone release in psychiatric patients and controls. Psychiatry Res. 1980;2:2536.Google ScholarPubMed
31. Abelson, J, Glitz, D, Cameron, O et al. , Blunted growth hormone response to clonidine in patients with generalized anxiety disorder. Arch Gen Psychiatry. 1991;48:157162.CrossRefGoogle ScholarPubMed
32. Yehuda, R, Siever, LJ, Teicher, MH. Plasma norepinephrine and 3-MHPG concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder. Biol Psychiatry. 1998;44:5663.CrossRefGoogle Scholar
33. Blanchard, EB, Kolb, LC, Prins, A, Gates, S, McCoy, GC. Changes in plasma norepinephrine to combat related stimuli among Vietnam veterans with posttraumatic stress disorder. J New Ment Dis. 1991;179:371373.CrossRefGoogle ScholarPubMed
34. Southwick, SM, Krystal, JH, Morgan, CA, Johnson, DR et al. , Abnormal noradrenergic function in posttraumatic stress disorder. Arch Gen Psychiatry. 1993;50:266274.CrossRefGoogle ScholarPubMed
35. Bremner, JD, Innis, RB, Ng, CK et al. , PET measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54:246256.CrossRefGoogle Scholar
36. Kolb, LC, Burns, BC, Griffiths, S. Propranolol and clonidine in the treatment of the chronic posttraumatic stress disorders of war. In: Van der Kolk, BA, ed. Posttraumatic Stress Disorder: Psychological and Biological Sequellae. Washington, DC: APA Press; 1984:98105.Google Scholar
37. Pliszka, S, McCracken, J, Maas, J. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry. 1996;35:264272.CrossRefGoogle ScholarPubMed
38. Arnsten, A. Development of the cerebral cortex: XIV. Stress impairs prefrontal cortical function. J Am Acad Child Adolesc Psychiatry. 1999;38:220222.Google Scholar
39. Faraone, SV, Biederman, J, Weiffenbach, B, Keith, T et al. , Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am J Psychiatry. 1999;456:768770.CrossRefGoogle Scholar
40. Ebstein, RP, Novick, O, Umansky, R, Priel, B et al. , Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nat Genet. 1996;12:7880.CrossRefGoogle Scholar
41. Lanau, F, Zenner, M, Civelli, O, Hartman, D. Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor. J Neurochem. 1997;68:804812.CrossRefGoogle ScholarPubMed
42. Zametkin, AJ, Rapoport, JL. Noradrenergic hypothesis of attention deficit disorder with hyperactivity: a critical review. In: Meltzer, HY, ed. Psychopharmacology: The Third Generation of Progress. New York, NY: Raven Press; 1987:837842.Google Scholar
43. Tatsumi, M, Groshan, K, Bakely, R, Richelson, E. Pharmacological profile of anti-depressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249258.Google Scholar
44. Casat, CD, Pleasants, DZ, Van Wyck Fleet, J. A double-blind trial of bupropion in children with attention deficit disorder. Psychopharmacol Bull. 1987;23:120122.Google ScholarPubMed
45. Hunt, RD, Minderaa, RB, Cohen, DJ. Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebocrossover therapeutic trial. J Am Acad Child Psychiatry. 1985;24:617629.CrossRefGoogle ScholarPubMed
46. Bierer, LM, Haroutunian, V, Gabriel, S et al. , Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64:749760.Google ScholarPubMed
47. Iversen, LL, Rossor, MN, Reynolds, GP et al. , Loss of pigmented dopamine-beta-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type. Neurosci Lett. 1983;39:95100.CrossRefGoogle ScholarPubMed
48. Peskind, ER, Wingerson, D, Murray, S et al. , Effects of Alzheimer's disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidine. Arch Gen Psychiatry. 1995;52:774782.CrossRefGoogle ScholarPubMed
49. Arnsten, AF, Goldman-Rakic, PS. Alpha2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science. 1985;230:12731276.CrossRefGoogle Scholar
50. Owens, MJ, Knight, DL, Nemeroff, CB. Paroxetine binding to the rat norepinephrine transporter in vivo. Biol Psychiatry. 2000;47:842845.CrossRefGoogle Scholar
51. Duncan, G, Paul, I, Powell, K et al. , Neuroanatomically selective down-regulation of B-adrenergic receptors by chronic imipramine treatment: relationships to the topography of 3H-imipramine and 3H-desipramine binding sites. J Pharmacol Exp Ther. 1989;248:470477.Google Scholar
52. Stanford, S, Nutt, D. Comparison of the effects of repeated electroconvulsive shock on a2 and B-adrenoceptors in different regions of rat brain. Neuroscience. 1982;7:17531757.CrossRefGoogle Scholar
53. Nestler, E, McMahon, A, Sabban, E et al. , Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus. Proc Natl Acad Sci U S A. 1990;87:75227526.CrossRefGoogle ScholarPubMed
54. Bremner, J, Randall, P, Scott, T et al. , MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152:973981.Google ScholarPubMed
55. McEwen, B. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105122.CrossRefGoogle ScholarPubMed
56. Ongur, D, Drevets, W, Price, J. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci. 1998;95:1329013295.CrossRefGoogle ScholarPubMed
57. Kitayama, I, Yaga, T, Kayahara, T et al. , Long-term stress degenerates, but imipramine regenerates, noradrenergic axons in the rat cerebral cortex. Biol Psychiatry. 1997;42:687696.CrossRefGoogle ScholarPubMed
58. Duman, R, Malberg, J, Thome, J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry. 1999;46:11811191.CrossRefGoogle ScholarPubMed