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Contribution of the stress-induced degeneration of the locus coeruleus noradrenergic neurons to the pathophysiology of depression: a study on an animal model

Published online by Cambridge University Press:  24 June 2014

Isao T. Kitayama ,
Masato Otani  and
Sumio Murase
Isao T. Kitayama*
Affiliation:
Kitayama Psychosomatic Clinic and Institute, Yokkaichi
Masato Otani
Affiliation:
Educational Faculty, Mie University, Tsu
Sumio Murase
Affiliation:
Department of Medical Informatics, Shinshu University Hospital, Matsumoto, Japan
*
Isao T. Kitayama, Kitayama Psychosomatic Clinic and Institute, Yokkaichi 510-0075, Japan
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Abstract

A novel theory on the pathophysiology of depression would be expected to resolve a contradiction between therapeutic time lag and monoamine hypothesis. On the basis of the fact that a subgroup of depression appears during or after stress, we exposed rats to a long-term (2 weeks) forced walking stress and produced depression-model rats in one group and spontaneous recovery rats in another. The density of axon terminals of the locus coeruleus (LC) neurons in the frontal cortex stained by dopamine β-hydroxylase antiserum was lower in the depression-model rats than in the spontaneous recovery rats and in the control rats without stress. The density was higher in the model rats daily treated with imipramine than in those treated with saline. Morphological projection (MP) index (a percentage of horseradish peroxidase-positive LC cells in total number of LC cells) and electrophysiological projection index (a percentage of LC neurons activated antidromically by electrical stimulation of the cerebral cortex) were lower in the depression-model rats than in the recovery and control rats. MP index was higher in the imipramine-treated rats than that in the saline-treated rats. Electron microscopic examination of the LC disclosed such degenerative changes as low-dense areas without structure, aggregation of intracellular organs, destroyed membranes around the rough endoplasmic reticulum (rER), a decreased number of deformed subsurface cisterns, glia invaginated into the LC neurons and prominent appearance of microglia containing increased number of lipofustin or lysosome in the model rats, but not in the spontaneous recovery rats. These findings suggest that the terminals and cell bodies of the LC noradrenergic neurons degenerate in the stress-induced depression-model rats and regenerate in the imipramine-treated model rats. This degenerative change may possibly contribute to the decrease in synthesis and metabolism of noradrenaline (NA), the slowing of axonal flow, the accumulation of NA in the neurons, the decrease in discharge rate of LC neurons without stress and the increase in release of NA in response to an additional stress. It may also explain the therapeutic time lag that is required to repair the noradrenergic neurons.

Keywords

degenerationdepression modelhypothesisimipraminelocus coeruleusnoradrenalineregenerationstress
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 16 , Issue 4 , August 2004 , pp. 190 - 199
Copyright
Copyright © 2004 Blackwell Munksgaard

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References

Schildkraut, JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965;122: 509–522.CrossRefGoogle ScholarPubMed
Lapin, IP, Oxenkrug, GF. Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1969;1: 132–136.DOI: 10.1016/S0140-6736(69)91140-4CrossRefGoogle ScholarPubMed
Coppen, A. The biochemistry of affective disorders. Br J Psychiatry 1967;113: 1237–1264.CrossRefGoogle ScholarPubMed
Bunney, WE. The current status of research in the catecholamine theories of affective disorders. Psychopharmacol Commun 1975;1: 599–609.Google ScholarPubMed
Shopsin, B, Gershon, S, Goldstein, M, Friedman, E, Wilk, S. Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun 1975;1: 239–249.Google ScholarPubMed
Shopsin, B, Wilk, S, Sathananthan, C, Gershon, S, Davis, K. Catecholamines and affective disorders. A critical assessment. J Nerv Ment Dis 1974;158: 369–383.CrossRefGoogle ScholarPubMed
Siever, LJ, Davis, KL. Overview: toward a dysregulation hypothesis of depression. Am J Psychiatry 1985;142: 1017–1031.Google Scholar
Banerjee, SP, Kung, LS, Riggi, SJ, Chanda, SK. Development of β-adrenergic receptor subsensitivity by antidepressants. 1977;268:455–457. Google Scholar
Vetulani, J, Sulser, F. Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature 1975;257: 495–496.CrossRefGoogle ScholarPubMed
Bremner, J, Narayan, M, Anderson, ER, Staib, LH, Miller, H, Charney, DS. Smaller hippocampal volume in major depression. Am J Psychiatry 2000;157: 115–117.CrossRefGoogle ScholarPubMed
Sheline, YI, Wany, P, Gado, MH, Csernansky, JG, Vannier, MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 1996;93: 3908–3913.DOI: 10.1073/pnas.93.9.3908CrossRefGoogle ScholarPubMed
McEwen, BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999;22: 105–122.DOI: 10.1146/annurev.neuro.22.1.105CrossRefGoogle ScholarPubMed
Gould, E, Tanapat, P, Hastings, NB, Shors, TJ. Neurogenesis in adulthood: a possible role in learning. Trends Cogn Sci 1999;3: 186–192.DOI: 10.1016/S1364-6613(99)01310-8CrossRefGoogle Scholar
McKinney, WT. Biobehavioral models of depression in monkeys. In: Hanin, I, Usdin, E, eds. Animal models in psychiatry and neurology. Oxford: Pergamon Press, 1977: 117–126. Google Scholar
Willner, P. The validity of animal models of depression. Psychopharmacology 1984;83: 1–16.DOI: 10.1007/BF00427414CrossRefGoogle ScholarPubMed
Kitayama, I, Yaga, T, Kayahara, Tet al. Long-term stress degenerates, but imipramine regenerates, noradrenergic axons in the rat cerebral cortex. Biol Psychiatry 1997;42: 687–696.DOI: 10.1016/S0006-3223(96)00502-1CrossRefGoogle ScholarPubMed
Sakashita, S, Otani, M, Kitayama, Iet al. Fine structure of the locus coeruleus in rats subjected to forced running stress. J Clin Electron Microsc 1988;21: 505–518. Google Scholar
Nakamura, S, Kitayama, I, Murase, S. Electrophysiological evidence for axonal degeneration of locus coeruleus neurons following long-term forced running stress. Brain Res Bull 1991;26: 759–763.DOI: 10.1016/0361-9230(91)90172-GCrossRefGoogle ScholarPubMed
Leonard, BE. Stress, norepinephrine and depression. J Psychiatry Neurosci 2001;26(Suppl.):S11–S16.Google ScholarPubMed
Stone, EA. Stress and catecholamines. In: Friedhoff, AJ, ed. Catecholamines and behavior, vol. 2. New York: Plenum Press, 1975: 31–72. CrossRefGoogle Scholar
Brady, LS. Stress, antidepressant drugs, and the locus coeruleus. Brain Res Bull 1994;35: 545–556.CrossRefGoogle ScholarPubMed
Kitayama, I, Koishizawa, M, Nomura, J, Hatotani, N, Nagatsu, I. Changes in behavior and central catecholamines in rats after long-term severe stress. In: Usdin, E, Kvetnansky, R, Axelrod, J, eds. Stress: the role of catecholamines and other neurotransmitters. New York: Gordon and Breach, 1984: 125–135. Google Scholar
Komori, T, Nomura, J, Inoue, K, Kitayama, I. Tyrosine hydroxylase activity in discrete brain regions of depression model rats. Jpn J Psychiatry 1990;44: 747–754. Google ScholarPubMed
Wang, P, Kitayama, I, Nomura, J. Tyrosine hydroxylase expression in the locus coeruleus of depression-model rats and rats exposed to short- and long-term forced walking stress. Life Sci 1998;62: 2083–2092.DOI: 10.1016/S0024-3205(98)00183-0CrossRefGoogle Scholar
Sakaguchi, T, Nakamura, S. Duration-dependent effects of repeated restraint stress on cortical projections of locus coeruleus neurons. Neurosci Lett 1990;118: 193–196.DOI: 10.1016/0304-3940(90)90624-ICrossRefGoogle ScholarPubMed
Ghadially, FN. Nuclear shape. In: Ghadially, FN, ed. Ultrastructural pathology of the cell and matrix. London: Butterworths, 1982: 2–7. Google ScholarPubMed
Kitayama, I, Cintra, A, Janson, AMet al. Chronic immobilization stress: evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male rat. J Neural Transm 1989;77: 93–130.CrossRefGoogle ScholarPubMed
Uno, H, Tarara, R, Else, JG, Suleman, MA, Sapolsky, RM. Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci 1989;9: 1705–1711.Google ScholarPubMed
Sapolsky, RM, Uno, H, Rebert, CS, Finch, CE. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 1990;10: 2897–2902.Google ScholarPubMed
Avanzino, GL, Ermirio, R, Cogo, CE, Ruggeri, P, Molinari, C. Effects of corticosterone on neurones of the locus coeruleus, in the rat. Neurosci Lett 1987;80: 85–88.DOI: 10.1016/0304-3940(87)90500-3CrossRefGoogle ScholarPubMed
Kostowski, W. Possible relationship of the locus coeruleus–hippocampal noradrenergic neurons to depression and mode of action of antidepressant drugs. Pol J Pharmacol Pharm 1985;37: 727–743.Google ScholarPubMed
Swanson, LW, Sawchenko, PE, Rivier, J, Vale, W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 1983;36: 165–186.CrossRefGoogle ScholarPubMed
Sakanaka, M, Shibasaki, T, Lederes, K. Corticotropin-releasing factor-like immunoreactivity in the rat brain as revealed by a modified cobalt-glucose oxide-diaminobenzidine method. J Comp Neurol 1987;260: 256–298.CrossRefGoogle ScholarPubMed
Valentino, RJ, Foote, SL, Aston-Jones, G. Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Brain Res 1983;270: 363–367.DOI: 10.1016/0006-8993(83)90615-7CrossRefGoogle ScholarPubMed
Zeng, J, Kitayama, I, Yoshizato, H, Zhang, K, Okazaki, Y. Increased expression of corticotropin-releasing factor receptor mRNA in the locus coeruleus of stress-induced rat model of depression. Life Sci 2003;73: 1131–1139.DOI: 10.1016/S0024-3205(03)00417-XCrossRefGoogle Scholar
Coffey, CE, Figiel, GS, Djang, WT, Weiner, RD. Subcortical hyperintensity on magnetic resonance imaging: a comparison of normal and depressed elderly subjects. Am J Psychiatry 1990;147: 187–189.Google ScholarPubMed
Dupont, RM, Jernigan, TL, Butters, Net al. Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging. Clinical and neuropsychological significance. Arch Gen Psychiatry 1990; 47: 55–59.CrossRefGoogle ScholarPubMed
Chan-Palay, V, Asan, E. Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression. J Comp Neurol 1989;287: 357–372.CrossRefGoogle Scholar
Hatotani, N, Nomura, J, Inoue, K, Kitayama, I. Psychoendocrine model of depression. Psychoneuroendocrinology 1979;4: 155–172.DOI: 10.1016/0306-4530(79)90029-5CrossRefGoogle Scholar
Sakashita, S, Otani, M. The fine structure of the locus coeruleus in forced running stress rat. J Clin Electron Microsc 1986;19: 614. Google Scholar
Rosenbluth, J. Subsurface cisterns and their relationship to the neuronal plasma membrane. J Cell Biol 1962;13: 405–421.DOI: 10.1083/jcb.13.3.405CrossRefGoogle ScholarPubMed
Suarez, I, Fernandez, B, Ardavin, CF. Lamellar body-subsurface cistern complexes in the paraventricular nuclei of the hamster. J Submicrosc Cytol 1983;15: 941–950.Google ScholarPubMed
Murase, S. Electrophysiological study on animal model of depression: single unit activity of locus coeruleus neurons in rats exposed to long-term severe stress. Mie Med J 1987;37: 1–15. Google Scholar
Simson, PE, Weiss, JM. Altered activity of the locus coeruleus in an animal model of depression. Neuropsychopharmacology 1988;1: 287–295.Google Scholar
Kitayama, I, Wang, P, Yamashita, Ket al. Noradrenergic function in depression-model rats. In: Nomura, J, ed. Neurobiology of depression and related disorders. Tsu: Mie Academic Press, 1998: 236–247. Google Scholar
Nisenbaum, LK, Zigmond, MJ, Sved, AF, Abercrombie, ED. Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J Neurosci 1991;11: 1478–1484.Google ScholarPubMed
Pacak, K, Armando, I, Fukuhara, Ket al. Noradrenergic activation in the paraventricular nucleus during acute and chronic immobilization stress in rats: an in vivo microdialysis study. Brain Res 1992;589: 91–96.DOI: 10.1016/0006-8993(92)91165-BCrossRefGoogle Scholar
Yamashita, K, Kitayama, I, Hamanaka, K, Nomura, J. Effect of reserpine on 3-methoxy-4-hydroxyphenylethyleneglycol and 3,4-dihydroxyphenylacetic acid in the hippocampus of depression-model rats: an in vivo microdialysis study. Brain Res 1998;785: 10–17.DOI: 10.1016/S0006-8993(97)01339-5CrossRefGoogle Scholar
Grant, MM, Weiss, JM. Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry 2001;49: 117–129.DOI: 10.1016/S0006-3223(00)00936-7CrossRefGoogle ScholarPubMed
Valentino, RJ, Curtis, AL. Antidepressant interactions with corticotropin-releasing factor in the noradrenergic nucleus locus coeruleus. Psychopharmacol Bull 1991;27: 263–269.Google ScholarPubMed
Valentino, RJ, Curtis, AL. Pharmacology of locus coeruleus spontaneous and sensory-evoked activity. Prog Brain Res 1991;88: 249–256.CrossRefGoogle ScholarPubMed
Nestler, EJ, McMahon, A, Sabban, EL, Tallman, JF, Duman, RS. Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus. Proc Natl Acad Sci USA 1990;87: 7522–7526.CrossRefGoogle ScholarPubMed
Brady, LS, Whitfield, HJ Jr, Fox, RJ, Gold, PW, Herkenham, M. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. J Clin Invest 1991;87: 831–837.CrossRefGoogle ScholarPubMed
Nakamura, S. Antidepressants induce regeneration of catecholaminergic axon terminals in the rat cerebral cortex. Neurosci Lett 1990;111: 64–68.DOI: 10.1016/0304-3940(90)90345-ACrossRefGoogle ScholarPubMed
Nakamura, S. Effects of mianserin and fluoxetine on axonal regeneration of brain catecholamine neurons. Neuroreport 1991;2: 525–528.CrossRefGoogle ScholarPubMed
Nakamura, S. Involvement of phospholipase A2 in axonal regeneration of brain noradrenergic neurones. Neuroreport 1993;4: 371–374.CrossRefGoogle ScholarPubMed
Nakamura, S. Effects of phospholipase A2 inhibitors on the antidepressant-induced axonal regeneration of noradrenergic locus coeruleus neurons. Microsc Res Tech 1994;29: 204–210.CrossRefGoogle ScholarPubMed
Duman, RS, Nakagawa, S, Malberg, J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 2001;25: 836–844.DOI: 10.1016/S0893-133X(01)00358-XCrossRefGoogle ScholarPubMed
Smith, MA, Makino, S, Altemus, Met al. Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus. Proc Natl Acad Sci USA 1995;92: 8788–8792.CrossRefGoogle ScholarPubMed