Serotonin (5-HT) in brains of adult patients with Down Syndrome

  • R. Seidl
  • S. T. Kaehler
  • H. Prast
  • N. Singewald
  • N. Cairns
  • M. Gratzer
  • G. Lubec
Conference paper


Down syndrome (DS) is a genetic disease with developmental brain abnormalities resulting in early mental retardation and precocious, age dependent Alzheimer-type neurodegeneration. Furthermore, non-cognitive symptoms may be a cardinal feature of functional decline in adults with DS. As the serotonergic system plays a well known role in integrating emotion, cognition and motor function, serotonin (5-HT) and its main metabolite, 5 hydroxyindol-3-acetic acid (5-HIAA) were investigated in post-mortem tissue samples from temporal cortex, thalamus, caudate nucleus, occipital cortex and cerebellum of adult patients with DS, Alzheimer’s disease (AD) and controls by use of high performance liquid chromatography (HPLC). In DS, 5-HT was found to be age-dependent significantly decreased in caudate nucleus by 60% (DS: mean ± SD 58.6 ± 28.2 vs. Co: 151.7 ± 58.4pmol/g wet tissue weight) and in temporal cortex by about 40% (196.8 ± 108.5 vs. 352.5 ± 183.0pmol/g), insignificantly reduced in the thalamus, comparable to controls in cerebellum, whereas occipital cortex showed increased levels (204.5 ± 138.0 vs. 82.1 ± 39.1 pmol/g). In all regions of DS samples, alterations of 5-HT were paralleled by levels of 5-HIAA, reaching significance compared to controls in thalamus and caudate nucleus. In AD, 5-HT was insignificantly reduced in temporal cortex and thalamus, unchanged in cerebellum, but significantly elevated in caudate nucleus (414.3 ± 273.7 vs. 151.7 ± 58.4pmol/g) and occipital cortex (146.5 ± 76.1 vs. 82.1 ± 39.1 pmol/g). The results of this study confirm and extend putatively specific 5-HT dysfunction in basal ganglia (caudate nucleus) of adult DS, which is not present in AD. These findings may be relevant to the pathogenesis and treatment of cognitive and non-cognitive (behavioral) features in DS.


High Performance Liquid Chromatography Down Syndrome Caudate Nucleus Occipital Cortex Down Syndrome Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andersson A, Sundman I, Marcusson J (1992) Age stability of human brain 5-HT terminals studied with 3H paroxetine binding. Gerontol 38: 127–132CrossRefGoogle Scholar
  2. Azmitia E, Whitaker-Azmitia P (1991) Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system. J Clin Psychiatry 52 [Suppl 12]: 4–16PubMedGoogle Scholar
  3. Bazelon M, Paine RS, Coeiw VA, Hunt P, Houck JC, Mahanand D (1967) Reversal of hypotonia in infants with Down’s syndrome by administration of 5-hydroxytry-ptophan. Lancet i: 1130–1133CrossRefGoogle Scholar
  4. Becker LE, Mito T, Takashima S, Onodera K (1991) Growth and development of the brain in Down syndrome. Prog Clin Biol Res 373: 133–152PubMedGoogle Scholar
  5. Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, Perl DP, Schmeidler J, Kanof P, Davis KL (1995) Neurochemical correlates of dementia severity in Alzheimer’s disease: relative importance of the cholinergic deficits. J Neurochem 64: 749–760PubMedCrossRefGoogle Scholar
  6. Bowen BB, Francis PT, Chessel IP, Webster MT (1994) Neurotransmission-the link integrating Alzheimer’s disease? Trends Neurosci 17: 149–150PubMedCrossRefGoogle Scholar
  7. Casper RC (1998) Serotonin, a major player in regulation of feeding and affect. Biol Psychiatry 44: 795–797PubMedCrossRefGoogle Scholar
  8. Celeda P, Artigas F (1993) Effects of local and systemic MAO inhibitors on extracellular brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the frontal cortex and raphe nuclei of freely moving rats. An in vivo microdialysis study. Naunyn Schmiedebergs Arch Pharmacol 347: 583–590CrossRefGoogle Scholar
  9. Chen CP, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, Jobst KA, Francis PT (1996) Presynaptic serotonergic markers in community-acquired cases of Alzheimer’s disease: correlations with depression and neuroleptic medication. J Neurochem 66:1592–1598PubMedCrossRefGoogle Scholar
  10. Coleman M (1971) Infantile spasms associated with 5-hydroxytryptophan administered in patients with Down’s syndrome. Neurol 21: 911CrossRefGoogle Scholar
  11. Epstein CJ (1995) Down Syndrome (Trisomy 21). In: Scriver SR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 749–794Google Scholar
  12. Frazer A, Hensler JG (1999) Serotonin. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry, molecular, cellular and medical aspects, 6th edn. Lippincott Raven, Philadelphia New York, pp 263–293Google Scholar
  13. Gedye A (1990) Dietary increase in serotonin reduces self-injurious behaviour in a Down’s syndrome adult. J Ment Defic Res 34: 195PubMedGoogle Scholar
  14. Gedye A (1991) Serotonergic treatment for aggression in a Down’s syndrome adult showing signs of Alzheimer’s disease. J Ment Defic Res 35: 247–258PubMedGoogle Scholar
  15. Geldmacher DS, Lerner AJ, Voci JM, Noelker EA, Somple LC, Whitehouse PJ (1997) Treatment of functional decline in adults with Down syndrome using seletive serotonin-reuptake inhibitor drugs. J Geriatr Psychiat Neurol 10: 99–104Google Scholar
  16. Godridge H, Reynolds GP, Czudek C, Calcutt NA, Benton M (1987) Alzheimer-like neurotransmitter deficits in adult Down’s syndrome brain tissue. J Neurol Neurosurg Psychiatry 50: 775–778PubMedCrossRefGoogle Scholar
  17. Gottfries CG, Adolfsson R, Aquilonius SM, Carlsson A, Eckernas SA, Nordberg A, Oreland L, Svennerholm L, Wiberg A, Winblad B (1983) Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT). Neurobiol Aging 4: 261–271PubMedCrossRefGoogle Scholar
  18. Haxby JV (1989) Neuropsychological evaluation of adults with Down’s syndrome: patterns of selective impairment in nondemented old adults. J Ment Defic Res 33: 193–197PubMedGoogle Scholar
  19. Holthoff-Detto K, Kessler J, Herholz K, Bonner H, Pietrzyk U, Wurker M, Ghaemi M, Wienhard K, Wagner R, Heiss WD (1997) Functional effects of striatal dysfunction in Parkinson disease. Arch Neurol 54: 145–150PubMedCrossRefGoogle Scholar
  20. Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72: 165–229PubMedGoogle Scholar
  21. Jacobs B, Fornai C (1995) Serotonin and behavior, a general hypothesis. In: Bloom F, Kupfer D (eds) Psychopharmacology: the fourth generation of progess. Raven Press, New York, pp 461–469Google Scholar
  22. Lauder JM (1993) Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci 16: 233–240PubMedCrossRefGoogle Scholar
  23. Lesch KP, Mössner R (1998) Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental and neurodgenerative disorders? Biol Psychiatry 44: 179–192PubMedCrossRefGoogle Scholar
  24. Li T, Holmes C, Sham PC, Vallada H, Birkett J, Kirov G (1997) Allelic functional variation of serotonin transporter expression is a susceptibility factor for late-onset Alzheimer’s disease. Neuroreport 8: 683–686PubMedCrossRefGoogle Scholar
  25. Lucki I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44: 151–162PubMedCrossRefGoogle Scholar
  26. Mann DMA, Yates PO (1986) Neurotransmitter deficits in Alzheimer’s disease and in other dementing disorders. Hum Neurobiol 5: 147–158PubMedGoogle Scholar
  27. Mann DMA, Yates PO, Marcyniuk B, Ravindra CR (1985) Pathological evidence for neurotransmitter deficits in Down’s syndrome of middle age. J Ment Defic Res 29: 125–135PubMedGoogle Scholar
  28. Mann DMA, Royston MC, Ravindra CR (1990) Some morphological observations on the brains of patients with Down’s syndrome: their relationship to age and dementia. J Neurol Sci 99: 153PubMedCrossRefGoogle Scholar
  29. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). II. Standardisation of the neuropatho-logical assessment of Alzheimer’s Disease. Neurol 41: 479–486CrossRefGoogle Scholar
  30. Nadel L, Epstein CJ (eds) (1992) Down Syndrome and Alzheimer disease. Wiley-Liss, New York (Prog Clin Biol Res 379)Google Scholar
  31. Palmer AM, Stratmann GC, Procter AW, Bowen DM (1988) Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 23: 616–620PubMedCrossRefGoogle Scholar
  32. Procter AW, Francis PT, Chen CPLH, Chessel IP, Dijk S, Clarke NA, Webster MT, Bowen DM (1995) The neurochemical pathology of Alzheimer’s disease. In: Allen SJ, Dawbarn D (eds) Neurobiolgy of Alzheimer disease. BIOS Scientific Publ, Oxford, pp 193–221Google Scholar
  33. Reynolds GP, Godridge H (1985) Alzheimer-like brain monoamine deficits in adults with Down’s syndrome. Lancet ii: 1368–1369CrossRefGoogle Scholar
  34. Risser D, Lubec G, Cairns N, Herrera-Marschitz M (1997) Excitatory amino acids and monoamines in parahippocampal gyrus and frontal cortical pole of adults with Down syndrome. Life Sci 60: 1231–1237PubMedCrossRefGoogle Scholar
  35. Rodriguez-Gomez JA, de la Roza C, Machado A, Cano J (1995) The effect of age on the monoamines of the hypothalamus. Mech Ageing Dev 77: 185–195PubMedCrossRefGoogle Scholar
  36. Singewald N, Kaehler S, Hemeida R, Philippu A (1997) Release of serotonin in the rat locus coeruleus: effects of cardiovascular, stressful and noxious stimuli. Eur J Neurosci 9: 556–562PubMedCrossRefGoogle Scholar
  37. Staley JK, Malison RT, Innis RB (1998) Imaging of the serotonergic system: interactions of neuroanatomical and functional abnormalities of depression. Biol Psychiatry 44: 534–549PubMedCrossRefGoogle Scholar
  38. Tierney MC, Fisher RH, Lewis AJ, Torzitto ML, Snow WG, Reid DW, Nieuwstraten P, Van Rooijen LAA, Derks HJGM, Van Wijk R, Bischop A (1998) The NINCDA-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer’s disease. Neurol 38: 359–364Google Scholar
  39. Tu JB, Zellweger H (1965) Blood-serotonin deficiency in Down’s syndrome. Lancet ii(7415): 715–716CrossRefGoogle Scholar
  40. Warren AC, Holroyd S, Folstein P (1989) Major depression in Down’s syndrome. Br J Psychiatry 155: 202–207PubMedCrossRefGoogle Scholar
  41. Weise P, Koch R, Shaw KNF, Rosenfeld MJ (1974) The use of 5-HTP in the treatment of Down’s syndrome. Pediatr 54: 165–167Google Scholar
  42. Wisniewski KE, Kida E (1994) Abnormal neurogenesis and synaptogenesis in Down syndrome brain. Dev Brain Dysfunct 7: 289–301Google Scholar
  43. Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down syndrome. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar
  44. Yates CM, Simpson J, Maloney AFJ, Gordon A, Reid AH (1980) Alzheimer-like cholinergic deficiency in Down syndrome. Lancet Nov 1st: 979Google Scholar
  45. Yates CM, Simpson J, Gordon A, Maloney AFJ, Allison Y, Ritchie IM, Urquhart A (1983) Catecholamines and cholinergic enzymes in pre-senile and senile Alzheimer-type dementia and Down’s syndrome. Brain Res 280: 119–126PubMedCrossRefGoogle Scholar
  46. Yates CM, Simpson J, Gordon A (1986) Regional brain 5-hydroxytryptamine levels are reduced in senile Down’s syndrome as in Alzheimer’s disease. Neurosci Lett 65:189–192PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • R. Seidl
    • 1
  • S. T. Kaehler
    • 3
  • H. Prast
    • 3
  • N. Singewald
    • 3
  • N. Cairns
    • 2
  • M. Gratzer
    • 1
  • G. Lubec
    • 1
  1. 1.Department of PediatricsUniversity of ViennaViennaAustria
  2. 2.Brain Bank, Institute of PsychiatryUniversity of LondonLondonUK
  3. 3.Department of Pharmacology and ToxicologyUniversity of InnsbruckAustria

Personalised recommendations