Abstract
Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12–18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.
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References
American Psychiatric Association. (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, DC, American Psychiatric Association
American Psychiatric Association. (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association
Barthelemy C, Bruneau N, Cottet-Eymard JM, Domenech-Jouve J, Garreau B, Lelord G, Muh JP, Peyrin L . (1988): Urinary free and conjugated catecholamine and metabolites in autistic children. J Autism Dev Disord 18: 585–591
Cheetham SC, Viggers JA, Slater NA, Heal DJ, Buckett WR . (1993): [3H]Paroxetine binding in rat frontal cortex strongly correlates with [3H]-5-HT uptake: Effect of administration of various antidepressant treatments. Neuropharmacology 32: 737–743
Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani HT . (1997): Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 42: 666–669
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT . (1999): Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 45: 287–295
Cook EH, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX . (1990): Autistic children and their first-degree relatives : Relationships between serotonin and norepinephrine levels and intelligence. J Neuropsych Clin Neurosci 2: 268–274
Cook E, Arora R, Anderson G, Berry-Kravis E, Yan S-Y, Yeoh H, Sklena P, Charak D, Leventhal B . (1993): Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder. Life Sci 52: 2005–2015
Cook E, Leventhal BL . (1996): The serotonin system in autism. Curr Opin Pediatr 8: 348–354
Cook EH, Chourchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal BL . (1997): Evidence of Linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 2: 247–250
D′Eufemia P, Finocchiaro R, Celli M, Viozzi L, Monteleone D, Giardini O . (1995): Low serum tryptophan to large amino acids ratio in idiopathic infantile autism. Biomed Pharmacother 49: 288–292
D′Hondt P, Maes M, Leysen J, Gommeren W, Scharpe S, Cosyns P . (1996): Seasonal variation in paroxetine binding to platelets in normal volunteers: Relationships to climatic factors. Neuropsychopharmacology 5: 187–198
Fernstrom JD . (1984): Tryptophan availability and serotonin synthesis in rat brain: Effects of experimental diabetes. In Schlossberger HG, Kochen W, Linzen B, Steinhart H (eds), Progress in Tryptophan and Serotonin Research. New York, NY, Walter de Gruyter, pp 161–172
Fichtner CG, Arora RC, O′Connor FL, Crayton JW . (1994): Platelet paroxetine binding and fluoxetine pharmacotherapy in posttraumatic stress disorder: Preliminary observations on a possible predictor of clinical treatment response. Life Sci 54: 39–44
Garnier C, Comoy E, Barthelemy C, Leddet I, Garreau B, Muh JP, Lelord G . (1986): Dopamine-betahyroxylase and homovanillic acid in autistic children. J Autism Dev Disord 16: 23–29
Gillberg C, Svennerholm L . (1987): CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry 151: 89–94
Habert E, Graham D, Tahraoui L, Claustre Y, Langer S . (1985): Characterization of [3H]-paroxetine binding to rat cortical membranes. Eur J Pharmacol 118: 107–114
Hamberger A, Gillberg C, Palm A, Hagberg B . (1982): Elevated CSF glutamate in Rett syndrome. Neuropediatrics 23: 212–213
Hanley HG, Stahl SM, Freeman DX . (1977): Hyperserotonemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry 34: 521–531
Hieble JP, Bondinell WE, Ruffolo RR . (1995): α- and β-adrenoceptors: From the gene to the clinic. I. Molecular biology and adrenoceptor classification. J Med Chem 38: 3415–3444
Hoffman BB, DeLean A, Wood CL, Schocken DD, Lefkowitz RJ . (1979): Alpha-adrenergic subtypes: quantitative assessment by ligand binding. Life Sci 24: 1739–1746
Hoshino Y, Yamamoto T, Kaneko M, Kumashiro H . (1986): Plasma free tryptophan concentration in autistic children. Brain Dev 8: 424–427
Jackson MJ, Garrod PJ . (1978): Plasma zinc, copper and amino acid levels in the blood of autistic children. J Autism Dev Disord 8: 203–208
Johnson RJ, Wiersema V, Kraft IA . (1974): Hair amino acids in childhood autism. J Autism Child Schizophr 4: 187–188
Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A . (1997): Serotonin transporter (5-HTT) gene variants associated with autism? Human Mol Genet 6 (13): 2233–2238
Lake CR, Ziegler MG, Murphy DL . (1977): Increased norepinephrine levels and decreased dopamine-beta-hydroxylase activity and primary autism. Arch Gen Psychiatry 34: 553–556
Launay JM, Bursztejn C, Ferrari P, Dreux C, Braconnier A, Zarifian E, Lancrenon S, Fermanian J . (1987): Catecholamine metabolism in infantile autism: A controlled study of 22 autistic children. J Autism Dev Disord 17: 333–347
Leboyer M, Bouvard MP, Launay JM . (1992): A double-blind study of naltrexone in infantile autism [Brief report]. J Autism Dev Disord 22: 309–319
Lesch KP, Wolozin BL, Murphy DL, Reiderer P . (1993): Primary structure of the human platelet serotonin uptake site: Identity with the brain serotonin transporter. J Neurochem 60: 2319–2322
Leventhal BL, Cook EH Jr, Morford M, Ravitz A, Freedman DX . (1990): Relationships of whole blood serotonin and plasma norepinephrine within families. J Autism Dev Disord 20: 499–511
Limberger N, Funk L, Trendelenburg AU, Starke K . (1995): Subclassification of presynaptic a2-adrenoceptors: a2-autoreceptors in rabbit atria and kidney. Naunyn-Schmiedeberg's Arch Pharmacol 352: 31–42
Maes M, Scharpe S, Cosyns P, Neels H, Stevens W, Bridts C, Thompson P, DeClerck L, D′Hondt P, DeMeyer F, Ranjan R, Meltzer HY, Peeters D, Wouters A, Cooreman W . (1994): Components of biological variation in serum activity of dipeptidyl peptidase IV and prolyl endopeptidase in normal man. Clin Chem 40: 1686–1691
Maes M, Scharpe S, Cosyns P, Neels H, Stevens W, Bridts C, Thompson P, DeClerck L, D′Hondt P, DeMeyer F, Ranjan R, Meltzer HY, Peeters D, Wouters A, Cooreman W . (1995): Components of biological variation, including seasonality in plasma L-tryptophan and competing amino-acids in man: Relationships to serum total protein, climatic variables and violent suicide occurrence. Arch Gen Psychiatry 52: 937–945
Maes M, Wauters A, Verkerk R, Neels H, van Gastel A, Cosyns P, Scharpe S, Desnyder R . (1996): Lower L-tryptophan availability in depression: A marker of a more generalized disorder in protein metabolism. Neuropsychopharmacology 15: 243–251
Maes M, van Gastel A, Delmeire L, Gommeren W, Leysen J . (1998): Decreased α2 receptor binding sites on platelets of depressed patients: Effects of tricyclic antidepressants and SSRIs. Biol Psychiatry 45: 278–284
Maes M, Lin A, Verkerk R, Delmeire L, van Gastel A, Gommeren W, Leysen J, Scharpe S . (1999): Serotonergic and noradrenergic markers of posttraumatic stress disorder: Lower affinity of platelet paroxetine and alpha-2 binding sites and increased plasma tyrosine availability to the brain. Neuropsychopharmacology 20: 188–197
Martineau J, Barthelemy C, Jouve J, Muh JP, Lelord G . (1992): Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: Age-related changes and drug effects. Dev Med Child Neurol 34: 593–603
McBride PA, Tierney H, DeMeo M, Chen JS, Mann JJ . (1990): Effects of age and gender on CNS serotonergic responsivity in normal adults. Biol Psychiatry 27: 1143–1155
McBride PA, Anderson GM, Hertzig ME, Snow ME, Thompson SM, Khait VD, Shapiro T, Cohen DJ . (1998): Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 37: 767–776
McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH . (1996a): Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 53: 993–1000
McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH . (1996b): A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 53: 1001–1008
Mellerup ET, Plenge P, Engelstoft M . (1983): High affinity binding of [3H]-paroxetine and [3H]-imipramine to human platelet membranes. Eur J Pharmacol 96: 303–309
Minderaa R, Anderson GM, Volkmar FR, Harcherick D, Akkerhuis GW, Cohen DI . (1989): Whole blood serotonin and tryptophan in autism: Temporal stability and effects of medication. J Autism Dev Disord 19: 129–136
Minderaa R, Anderson GM, Volkmar FR, Akkerhuis GW, Cohen DI . (1994): Noradrenergic and adrenergic functioning in autism. Biol Psychiatry 36: 237–241
Moir ATB, Eccleston D . (1968): The effect of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 15: 1093–1108
Moller SE . (1986): Plasma neutral amino acids and food preferences: Possible implications in normals and depressives. Biblthca Nutr Dieta 38: 149–153
Pardridge WM . (1979): Tryptophan transport through the blood-brain barrier: In vivo measurement of free and albumin-bound amino acid. Life Sci 25: 1519–1528
Perry TL, Hansen S, Christie RG . (1978): Amino compounds and organic acids in CSF, plasma and urine of autistic children. Biol Psychiatry 13: 575–586
Riddle MA, Anderson GM, McIntosh S, Harcherick DF, Shaywitz BA, Cohen DJ . (1986): Cerebrospinal fluid monoamine precursor and metabolite levels in children treated for leukemia: Age and sex effects and individual variability. Biol Psychiatry 21: 69–83
Salter M, Pogson CI . (1987): The importance of the liver as a regulator of amino acid supply to the brain. In Huether G (ed), Amino Acid Availability and Brain Function in Health and Disease. Berlin, Germany, Springer-Verlag, pp 21–28
Schain RJ, Freedman DX . (1996): Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatrics 58: 315–320
Sneddon JM . (1973): Blood platelets as a model for monoamine-containing neurons. Progr Neurobiol 1: 151–198
Stahl SM . (1977): The human platelet: A diagnostic and research tool for the study of biogenic amines in psychiatry and neurologic disorders. Arch Gen Psychiatry 34: 509–516
Stahl SM . (1985): Peripheral models for the study of neurotransmitter receptors in man. Psychopharmacol Bull 21: 663–671
Szatmari P . (1999): Heterogeneity and the genetics of autism. J Psychiatry Neurosci 24: 159–165
Turnell D, Cooper J . (1982): Rapid assay for amino acids in serum or urine by precolumn derivatisation and reversed-phase liquid chromatography. Clin Chem 28: 527–531
Voog L, Eriksson T . (1992): Relationship between plasma and brain large neutral amino acids in rats fed diets with different compositions at different times of the day. J Neurochem 59: 1868–1874
Visconti P, Piazzi S, Posar A, Santi A, Pipitone E, Rossi PG . (1994): Amino acids and infantile autism. Dev Brain Dysf 7: 86–92
Weizman A, Gonen N, Tyano S, Szekely GA, Rehavi M . (1987): Platelet [3H]imipramine binding in autism and schizophrenia. Psychopharmacology 91: 101–103
Winsberg BG, Sverd J, Castells S, Hurwic M, Perel JM . (1980): Estimation of monoamine and cyclic-AMP turnover and amino-acid concentrations of spinal fluid in autistic children. Neuropediatrics 11: 250–255
Young JG, Cohen DJ, Brown SL, Caparulo BK . (1978): Decreased urinary free catecholamines in childhood autism. J Am Acad Child Psychiatry 17: 671–678
Young JG, Cohen DJ, Kavanagh ME, Landis HD, Shaywitz BA, Maas JW . (1981): Cerebrospinal fluid, plasma and urinary MHPG in children. Life Sci 28: 2837–2845
Yuwiler A, Oldendorf WH, Geller E, Braun L . (1977): The effect of albumin binding and amino acid composition on tryptophan uptake into the brain. J Neurochem 28: 1015–1023
Acknowledgements
This research was supported in part by the Clinical Research Center for Mental Health (CRC-MH) and the Janssen Research Foundation, Beerse, Belgium. We would like to thank W. Gommeren, R.T., and Prof. Dr. J. Leysen of the Janssen Research foundation, ‘De Speling’ (a Treatment Centre For Autistic Youngsters, Booischot, Belgium), the L.S.A. (an association of parents of children with autism in Limburg, Belgium), and Mrs. M. Elseviers, Department of Nephrology, University of Antwerp, Wilrijk, Belgium.
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Croonenberghs, J., Delmeire, L., Verkerk, R. et al. Peripheral Markers of Serotonergic and Noradrenergic Function in Post-Pubertal, Caucasian Males with Autistic Disorder. Neuropsychopharmacol 22, 275–283 (2000). https://doi.org/10.1016/S0893-133X(99)00131-1
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DOI: https://doi.org/10.1016/S0893-133X(99)00131-1
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