Neuropediatrics 2002; 33(3): 142-149
DOI: 10.1055/s-2002-33678
Original Article

Georg Thieme Verlag Stuttgart · New York

Alteration of Serotonergic Receptors in the Brain Stems of Human Patients with Respiratory Disorders

Y. Ozawa1 , N. Okado2
  • 1 Department of Neonatology, Toho University School of Medicine, Ohta, Tokyo, Japan
  • 2 Neurobiology Laboratory, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
Further Information

Publication History

Received: 16 November 2001

Accepted after Revision: 11 March 2002

Publication Date:
18 September 2002 (online)

Abstract

We compared the developmental changes of 5-hydroxytryptamine (5-HT) 1 A and 5-HT2 A receptor immunoreactivity in the nuclei in relation to the cardiorespiratory or autonomic function in the human brain stem in sudden infant death syndrome (SIDS) and congenital central hypoventilation syndrome (CCHS) patients and age-matched controls by means of immunohistochemical methods. There were significant decreases in 5-HT1 A and 5-HT2 A receptor immunoreactivity in the dorsal nucleus of the vagus, solitary nucleus and ventrolateral medulla in the medulla oblongata, and significant increases in the periaqueductal gray matter (PAG) of the midbrain in SIDS victims, but there were no significant differences between those in CCHS patients and controls. The decreased immunoreactivity of the receptors in the medulla oblongata was accompanied by brain stem gliosis. Therefore, the decreases in the receptors may be secondary to chronic hypoxia or repeated ischemia, but may be causally related to some impairment of the developing cardiorespiratory neuronal system. As 5-HT1 A and 5-HT2 A receptors were the most abundant in the fetal period and then decreased with subsequent development, the increases in 5-HT1 A and 5-HT2 A receptor immunoreactivity in PAG may reflect delayed neuronal maturation, but may also reflect compensatory changes in response to hypofunctioning serotonergic neurons in the medulla oblongata in SIDS. There was no abnormal expression of 5-HT1 A and 5-HT2 A receptors in CCHS brain stems, and so the pathophysiology seems to be different between SIDS and CCHS patients.

References

  • 1 Amiel J, Salomon R, Attie T, Pelet A, Trang H, Mokhtari M. et al . Mutations of the RET-GDNF signaling pathway in Ondine's curse.  Am J Hum Genet. 1998;  62 715-717
  • 2 Armstrong D, Sachis P, Bryan C, Becker L. Pathological features of persistent infantile sleep apnea with reference to the pathology of sudden infant death syndrome.  Ann Neurol. 1982;  12 169-174
  • 3 Becker L E. Neural maturational delay as a link in the chain of events leading to SIDS.  Can J Neurol Sci. 1990;  17 361-371
  • 4 Becker L E, Takashima S. Chronic hypoventilation and development of brain stem gliosis.  Neuropediatrics. 1985;  16 19-23
  • 5 Beitz A J. Central gray. Paxinos G The Human Central Nervous System. San Diego; Academic Press Inc 1990: 307-320
  • 6 Bergstrom L, Lagercrantz H, Terenius L. Post-mortem analysis of neuropeptides in brains from sudden infant death victims.  Brain Res. 1984;  323 279-285
  • 7 Commare M C, Franois B, Estournet B, Barois A. Ondine's curse: a discussion of five cases.  Neuropediatrics. 1993;  24 313-318
  • 8 DeArmond S J, Fusco M M, Dewey M M. Structure of the Human Brain. A Photographic Atlas. Vol. 3. Coronal Sections of the Gross Brain and Brain stem. 3rd ed. New York; Oxford University Press 1989: 36-61
  • 9 Denoroy L, Gay N, Gilly R, Tayot J, Pasquier B, Kopp N. Catecholamine synthesizing enzyme activity in brainstem areas from victims of sudden infant death syndrome.  Neuropediatrics. 1987;  18 187-190
  • 10 Di Pasquale E, Morin D, Monteau R, Hilaire G. Serotonergic modulation of the respiratory rhythm generator at birth: an in vitro study in the rat.  Neurosci Lett. 1992;  143 91-95
  • 11 Filiano J J, Kinney H C. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model.  Biol Neonate. 1994;  65 194-197
  • 12 Folgering H, Kuyper F, Kille J F. Primary alveolar hypoventilation (Ondine's curse syndrome) in an infant without an external arcuate nucleus. Case report.  Bull Europ Physiopath Resp. 1979;  15 659-665
  • 13 Guilleminault C, Ariagno R, Korobkin R, Nagel L, Baldwin R, Coons S. et al . Mixed and obstructive sleep apnea and near miss for sudden infant death syndrome. 2. Comparison of near miss and normal control infant by age.  Pediatrics. 1979;  64 882-891
  • 14 Haddad G G, Mazza N M, Defendini R, Blanc W A, Driscoll J M, Epstein M AF. et al . Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate.  Medicine. 1978;  57 517-526
  • 15 Hamada S, Senzaki K, Hamaguchi-Hamada K, Tabuchi K, Yamamoto H, Yamamoto T. et al . Localization of 5-HT2A receptor in rat cerebral cortex and olfactory system revealed by immunohistochemistry using two antibodies raised in rabbit and chicken.  Mol Brain Res. 1998;  54 199-211
  • 16 Harper R M, Ni H, Zhang J. Discharge relationships of periaqueductal gray neurons to cardiac and respiratory patterning during sleep and waking states. Depaulis A, Bandler R The Midbrain Periaqueductal Gray Matter. New York; Plenum Press 1991: 41-55
  • 17 Harper R M, Leake B, Hoffman H, Walter D O, Hoppenbrouwers T, Hodgman J. et al . Periodicity of sleep states is altered in infants at risk for the sudden infant death syndrome.  Science. 1981;  213 1030-1033
  • 18 Hilaire G, Monteau R, Gauthier P, Rega P, Morin D. Functional significance of the dorsal and ventral respiratory group in adult and newborn rats: in vivo and in vitro studies.  Neurosci Lett. 1990;  111 133-138
  • 19 Hoyer D, Clarke D E, Fozard J R, Hartig P R, Martin G R, Mylecharane E J. et al . International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin).  Pharmacol Rev. 1994;  46 157-203
  • 20 Hunt C E. Impaired arousal from sleep: relationship to sudden infant death syndrome.  J Perinatol. 1989;  9 184-187
  • 21 Jiang M, Chandler S D, Ennis M, Shipley M T, Behbehani M M. Actions of epinephrine on neurons in the rat midbrain periaqueductal gray matter maintained in vitro.  Brain Res Bull. 1992;  29 871-877
  • 22 Kinney H C, Burger P C, Harrell F E, Hudson R P. “Reactive gliosis” in the medulla oblongata of victims of the sudden infant death syndrome.  Pediatrics. 1983;  72 181-187
  • 23 Kinney H C, Brody B A, Finkelstein S P, Vawter G F, Mandell F, Gilles F H. Delayed central nervous system myelination in the sudden infant death syndrome.  J Neuropathol Exp Neurol. 1991;  50 29-48
  • 24 Kinney H C, Filiano J J, Harper R M. The neuropathology of the sudden infant death syndrome. A review.  J Neuropathol Exp Neurol. 1992;  51 115-126
  • 25 Kopp N, Chigr F, Denoroy L, Gilly R, Jordan D. Absence of adrenergic neurons in nucleus tractus solitarius in sudden infant death syndrome.  Neuropediatrics. 1993;  24 25-29
  • 26 Kopp N, Denoroy L, Eymin C, Gay N, Richard F, Awano K. et al . Studies of neuroregulators in the brain stem of SIDS.  Biol Neonate. 1994;  65 189-193
  • 27 Lalley P M, Bischoff A-M, Richter D W. 5-HT1 A receptor-mediated modulation of medullary expiratory neurons in the cat.  J Physiol. 1994;  476 117-130
  • 28 Lalley P M, Bischoff A-M, Schwarzacher S W, Richter D W. 5-HT2 receptor-controlled modulation of medullary respiratory neurons.  J Physiol. 1995;  487 653-661
  • 29 Liu H M, Loew J M, Hunt C E. Congenital central hypoventilation syndrome . a pathologic study of the neuromuscular system.  Neurology. 1978;  28 1013-1019
  • 30 Martin G R, Humphery P PA. Receptors for 5-hydroxytryptamine: current perspectives on classification and nomenclature.  Neuropharmacology. 1994;  33 261-273
  • 31 McCall R B, Clement M E. Roles of serotonin 1 A and serotonin 2 receptors in the central regulation of the cardiovascular system.  Pharmacol Rev. 1994;  46 231-243
  • 32 Morilak D A, Ciaranello R D. Ontogeny of 5-hydroxytryptamine 2 receptor immunoreactivity in the developing rat brain.  Neurosci. 1993;  55 869-880
  • 33 Nieuwenhuys R, Voogd J, van Huijzen J. The Human Central Nervous System. A Synopsis and Atlas. Part IV: Microscopical Sections. Transverse Sections Through the Brain Stem and Spinal Cord. 3rd ed. Berlin; Springer-Verlag 1988: 104-141
  • 34 Obonai T, Yasuhara M, Nakamua T, Takashima S. Catecholamine neurons alteration in the brain stem of sudden infant death syndrome victims.  Pediatrics. 1998;  101 283-288
  • 35 Obonai T, Takashima S, Becker L E, Asanuma M, Mizuta R, Horie H. et al . Relationship of substance P and gliosis in medulla oblongata in neonatal sudden infant death syndrome.  Pediatr Neurol. 1996;  15 189-192
  • 36 Panigrahy A, Filiano J, Sleeper L A, Mandell F, Valdes-Dapena M, Krous H F. et al . Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome.  J Neuropathol Exp Neurol. 2000;  59 377-384
  • 37 Poceta J S, Strandjord T P, Badura R J, Milstein J M. Ondine's curse and neurocristopathy.  Pediatr Neurol. 1987;  3 370-372
  • 38 Quattrochi J J, McBride P T, Yates A J. Brainstem immaturity in sudden infant death syndrome: a quantitative rapid Golgi study of dendritic spines in 95 infants.  Brain Res. 1985;  325 39-48
  • 39 Saito Y, Itoh M, Ozawa Y, Obonai T, Kobayashi Y, Washizawa K. et al . Changes of neurotransmitters in the brainstem of patients with respiratory-pattern disorders during childhood.  Neuropediatrics. 1999;  30 133-140
  • 40 Takashima S, Armstrong D, Becker L E, Huber J. Cerebral white matter lesions in the sudden infant death syndrome.  Pediatrics. 1978;  62 155-159
  • 41 Takashima S, Armstrong D, Becker L E, Bryan C. Cerebral hypoperfusion in the sudden infant death syndrome? Brain stem gliosis and vasculature.  Ann Neurol. 1978;  4 257-262
  • 42 Takashima S, Becker L E. Prenatal and postnatal maturation of medullary “respiratory centers”.  Dev Brain Res. 1986;  26 173-177
  • 43 Takashima S, Becker L E. Developmental abnormalities of medullary respiratory centers in sudden infant death syndrome.  Exp Neurol. 1985;  90 580-587
  • 44 Weese-Mayer D E, Silvestri J M, Menzies L J, Morrow-Kenny A S, Hunt C E, Hauptman S A. Congenital central hypoventilation syndrome: diagnosis, management, and long-term outcome in thirty-two children.  J Pediatr. 1992;  120 381-387
  • 45 Willinger M, James L S, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development.  Pediatr Pathol. 1991;  11 677-684
  • 46 Yamanouchi H, Takashima S, Becker L E. Correlation of astrogliosis and substance P immunoreactivity in the brainstem of victims of sudden infant death syndrome.  Neuropediatrics. 1993;  24 200-203
  • 47 Zec N, Filano J J, Panigraphy A, White W F, Kinney H C. Developmental changes in [3H]lyserigic acid diethylamine ([3H]LSD) binding to serotonin receptors in the human brainstem.  J Neuropathol Exp Neurol. 1996;  55 114-126

M. D. Yuri Ozawa

Department of Neonatology
Toho University School of Medicine

6 - 11 - 1, Ohmorinishi, Ohta

Tokyo 143 - 8541

Japan

Email: hy_ozawa@d6.dion.ne.jp