In Vivo Methods for the Rate of Serotonin Synthesis and Axonal Transport Measurements in the Brain

  • Mirko Diksic


For more than twenty years researchers have been searching for a method of measuring the rate of brain serotonin synthesis which is both convenient and anatomically precise. Serotonin (5-hydroxytryptamine; 5-HT) is a neuro-transmitter widely distributed in the brain. It has been implicated in many brain functions (e.g. sleep cycle: Jouvet, 1967; food intake: Blundell and Hill, 1987) and in disorders ranging from migraine (e.g. Andersen and Dafny, 1983) to schizophrenia (e.g. Sedvall, 1981) and depression (e.g. Young et al., 1981). To date it has been impossible to measure serotonin synthesis rate in living human brain, although it has often been determined in laboratory animals in a ‘normal’ state and under the influence of various drugs. All procedures developed to date are fatal and therefore obviously not useful in humans. Attempts have been made to measure the neurotransmitter concentration in post-mortem human brain (e.g. Dodd et al., 1988). However, although these measurements might provide information on the steady state concentration of 5-HT, they cannot give any information about the 5-HT synthesis rate. And, of course, there is always the possibility of post-mortem changes.


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  1. Adell, A., Garcia-Marquez, C., Armario, A. and Gelpi, E. (1988). Chronic stress increases serotonin and noradrenalin in rat brain and sensitizes their responses to a further acute stress. J. Neurochem. 50, 1676–1681CrossRefGoogle Scholar
  2. Aghajanian, G. K., Bloom, F. E., Lovel, R., Sheard, M. and Freedman, D. X. (1966). The uptake of 5-hydroxytryptamine-3H from cerebral ventricles: autoradiographic localization. Biochem. Pharmacol., 15, 1401–1403CrossRefGoogle Scholar
  3. Andersen, E. and Dafhy, N. (1983). An ascending serotonergic pain modulation pathway from the dorsal raphe nucleus to the parafascicularis nucleus of the thalamus. Brain Res., 269, 57–67PubMedCrossRefGoogle Scholar
  4. Araneda, S., Bobillier, P., Buda, M. and Pujol, J.-F. (1980). Retrograde axonal transport following injection of [3H]serotonin in the olfactory bulb. I. Biochemical study. Brain Res., 196, 405–415PubMedCrossRefGoogle Scholar
  5. Awazi, N. and Guldberg, H. C. (1978). On the interaction of 5-hydroxytryptophan and 5-hydroxytryptamine with dopamine metabolism in the rat striatum. Naunyn-Schmeidbergs Arch. Pathol Exp. Pharmakol., 303, 63–72CrossRefGoogle Scholar
  6. Azmitia, E. C. and Segal, M. (1978). An autographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J. Comp. Neurol., 179, 641–668PubMedCrossRefGoogle Scholar
  7. Barondes, S. H. (1974). Do tryptophan concentrations limit protein synthesis at specific sites in the brain? In Aromatic Amino Acids in the Brain. Elsevier, New York, pp. 265–574Google Scholar
  8. Baumann, P. (1975). Metabolism of 5-hydroxytryptophan-14C after intracisternal injection with and without the influence of drugs in the rat brain. Psychopharmacologia (Berl.), 45, 39–45CrossRefGoogle Scholar
  9. Beaudet, A. and Descarries, L. (1976). Quantitative data on serotonin nerve terminals in adult rat neocortex. Brain Res., 111, 301–309PubMedCrossRefGoogle Scholar
  10. Beaudet, A. and Descarries, L. (1979). Radioautographic characterization of a serotonin-accumulating nerve cell group in adult rat hypothalamus. Brain Res., 160, 231–243PubMedCrossRefGoogle Scholar
  11. Bevington, P. R. (1969). Data Reduction and Error Analysis for the Physical Sciences. McGraw-Hill, New York, pp. 92–1Google Scholar
  12. Blundell, J. E. and Hill, A. J. (1987). Influence of tryptophan on appetite and food selection in man. In Amino Acids in Health and Disease: New Prospectives (ed. S. Kaufman). Alan R. Liss, New York, pp. 403–419Google Scholar
  13. Bobillier, P., Petitjean, F., Salvert, D., Ligier, M. and Seguin, S. (1975). Differential projections of the nucleus raphe dorsalis and nucleus raphe centralis as revealed by autoradiography. Brain Res., 85, 205–210PubMedCrossRefGoogle Scholar
  14. Bobillier, P., Sequin, S., Petitjean, F., Salvert, D., Touret, M. and Michel, J. (1976). The raphe nuclei of the cat brain stem: a topographic atlas of their efferent projections as revealed by autoradiography. Brain Res., 113, 449–486PubMedCrossRefGoogle Scholar
  15. Bowsher, P. R. and Henry, D. P. (1986). Aromatic L-amino acid decarboxylase. In Neuromethods; Neurotransmitter Enzymes, Vol. 5 (ed. A. A. Boulton, G. B. Baker and P. H. Yu). Humana Press, Clifton, NJ, pp. 33–78CrossRefGoogle Scholar
  16. Bulat, M., Iskic, S., Stančic, L., Kveder, S. and Živkovic, B. (1970). Formation of 5-hydroxytryptophol from exogenous 5-hydroxytryptamine in cat spinal cord in vivo. J. Pharm. Pharmacol, 22, 67–68PubMedCrossRefGoogle Scholar
  17. Burton, A. C. (1936). The basis of the master reaction in biology. J. Cell Comp. Physiol, 9, 1–14CrossRefGoogle Scholar
  18. Carlsson, A., Kehr, W. and Lindqvist, M. (1976). The role of intraneuronal amine levels in the feedback control of dopamine, noradrenaline and 5-hydroxytryptamine synthesis in rat brain. J Neur. Transmiss., 39, 1–19CrossRefGoogle Scholar
  19. Chaly, T. and Diksic, M. (1988). Synthesis of ‘no-carrier-added’ a-[11C]methyl-L-tryptophan. J Nucl. Med., 29, 370–374PubMedGoogle Scholar
  20. Christensen, H. N. and Handlogten, M. E. (1979). Interaction between parallel transport systems examined with tryptophan and related amino acids. J Neur. Transmiss. Supp., 15, 1–13Google Scholar
  21. Coppen, A., Shaw, D. M. and Farrell, M. B. (1963). Potentiation of the antidepressive effect of a monoamine oxidase inhibitor by tryptophan. Lancet, 1, 79–81PubMedCrossRefGoogle Scholar
  22. Čulman, J., Kiss, A. and Kvetnansky, R. (1984). Serotonin and tryptophan hydroxylase in isolated hypothalamic and brain stem nuclei of rats exposed to acute and repeated immobilizaion stress. Exp. Clin. Endocrinol., 83, 28–36PubMedCrossRefGoogle Scholar
  23. Curzon, G., Friedel, J. and Knott, P. J. (1973). The effects of fatty acids on the binding of tryptophan to plasma protein. Nature, 242, 198–200PubMedCrossRefGoogle Scholar
  24. Curzon, G. and Green, A. R. (1969). Effects of immobilization on rat liver tryptophan pyrrolase and 5-hydroxytryptamine metabolism. Br. J. Pharmacol, 37, 689–697PubMedPubMedCentralCrossRefGoogle Scholar
  25. Curzon, G., Joseph, M. H. and Knott, P. J. (1972). Effects of immobilization and food deprivation on rat brain tryptophan metabolism. J. Neurochem., 19, 1967–1974PubMedCrossRefGoogle Scholar
  26. Curzon, G. and Marsden, C. A. (1975). Metabolism of a tryptophan load in the hypothalamus and other brain regions. J. Neurochem., 25, 251–256PubMedCrossRefGoogle Scholar
  27. Dählström, A. and Häggendal, J. (1973). Localization and transport of serotonin. In Serotonin and behavior (ed. J. Barchas and E. Usdin). Academic Press, New York, pp. 87–96Google Scholar
  28. Davis, V. E., Cashaw, J. L., Huff, J. A. and Brown, H. (1966). Identification of 5-hydroxytryptophol as a serotonin metabolite in man. Proc. Soc. Exp. Biol Med., 122, 890–893PubMedCrossRefGoogle Scholar
  29. Diksic, M., Nagahiro, S., Chaly, T., Sourkes, T. L., Yamamoto, Y. L. and Feindel, W. (1990a). The serotonin synthesis rate measured in living dog brain by PET. J. Neurochem. In pressGoogle Scholar
  30. Diksic, M., Nagahiro, S., Sourkes, T. L. and Yamamoto, Y. L. (1990b). A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model. J. Cereb. Blood Flow Metab., 10, 1–12PubMedCrossRefGoogle Scholar
  31. Diksic, M. and Sourkes, T. L. (1990). Autoradiographic measurement of the rate of serotonin synthesis in the rat brain. Proceedings of ISTRY-89 (In press)Google Scholar
  32. Diksic, M., Sourkes, T. L., Nagahiro, H., Chary, T. and Missala, K. (1988). Influence of plasma tryptophan and PaCO2 on brain serotonin synthesis in dog as measured with PET. J. Nucl. Med., 29, 784Google Scholar
  33. Diksic, M., Sourkes, T. L., Nakai, H., Chaly, T., Missala, K. and Yamaimoto, Y. L. (1987). In vivo rate of serotonin synthesis in the dog brain measured by positron emission tomography. Proceedings of the 17th Annual Meeting of the Society for Neuroscience, Abstract No. 224.5Google Scholar
  34. Dodd, P. R., Hambley, J. W., Cowburn, R. F. and Hardy, J. A. (1988). A comparison of methodologies for the study of functional transmitter neurochemistry in human brain. J. Neurochem., 50, 1333–1345, and references thereinPubMedCrossRefGoogle Scholar
  35. Doucet, G., Descarries, L., Audet, M. A., Garcia, S. and Berger, B. (1988). Radioautographic method for quantifying regional monoamine innervations in the rat brain. Application to the cerebral cortex. Brain Res., 441, 233–259PubMedCrossRefGoogle Scholar
  36. Duda, N. J. and Moore, K. E. (1985). Simultaneous determination of 5-hydroxytryptophan and 3,4-dihydroxyphenylalamine in rat brain by HPLC with electrochemical detection following electrical stimulation of the dorsal raphe nucleus. J. Neurochem., 44, 128–133PubMedCrossRefGoogle Scholar
  37. Ehret, M., Gobaille, S., Cash, C. D., Mandel P. and Maitre, M. (1987). Regional distribution in rat brain of tryptophan hydroxylase apoenzyme determined by enzyme-linked immunoassay. Neurosci. Lett., 73, (1), 71–76PubMedCrossRefGoogle Scholar
  38. Etienne, P., Young, S. N. and Sourkes, T. L. (1976). Inhibition by albumin of tryptophan uptake by rat brain. Nature, 262, 144–145PubMedCrossRefGoogle Scholar
  39. Evans, A. C., Diksic, M., Yamamoto, Y. L., Kato, A., Dagher, A., Redies, C. and Hakim, A. (1986). Effect of vascular activity in the determination of rate constants for the uptake of 18F-labelled 2-fluoro-2-deoxy-D-glucose: error analysis and normal values in older subjects. J. Cereb. Blood Flow Metab., 6, 724–738PubMedCrossRefGoogle Scholar
  40. Fernstrom, J. D. (1983). Role of precursor availability in control of monoamine biosynthesis in brain. Physiol. Rev., 63, 485–546Google Scholar
  41. Fibiger, H. C., McGeer, E. G. and Atmadja, S. (1973). Axoplasmic transport of dopamine in nigrostriatal neurons. J. Neurochem., 21, 373–385PubMedCrossRefGoogle Scholar
  42. Finkelstein, L. and Carson, E. R. (1985). In Mathematical Modelling of Dynamic Biological Systems. Wiley, New York, pp. 51–Google Scholar
  43. Fowler, C. J. and Tipton, K. F. (1982). Deamination of 5-hydroxytryptamine by both forms of monoamine oxidase by the rat brain. J. Neurochem., 38, 733–736PubMedCrossRefGoogle Scholar
  44. Frankfurt, M. and Azmitia, E. (1984). Regeneration of serotonergic fibres in the rat hypothalamus following unilateral 5,7-dihydroxytryptamine injection. Brain Res., 298, 273–282PubMedCrossRefGoogle Scholar
  45. Friedlander, G., Kennedy, J. W. and Miller, J. M. (1955). Nuclear and Radiochemistry, pp. 69–85Google Scholar
  46. Friedman, P. A., Kappelman, A. H. and Kaufman, S. (1972). Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain. J. Biol. Chem., 247, 4165–4173PubMedGoogle Scholar
  47. Gal, E. M. and Christiansen, P. A. (1975). Alpha-methyltryptophan: Effects on cerebral monooxygenases in vitro and in vivo. J. Neurochem., 24, 89–95PubMedCrossRefGoogle Scholar
  48. Gal, E. M. and Sherman, A. D. (1978). Synthesis and metabolism of L-kynurenine in rat brain. J. Neurochem., 30, 607–613PubMedCrossRefGoogle Scholar
  49. Gess, G. L. and Tagliamonte, A. (1974). Serum free tryptophan: control of brain concentrations of tryptophan and of synthesis of 5-hydroxytryptamine. In: Aromatic Amino Acids in the Brain. Elsevier, New York, pp. 205–216Google Scholar
  50. Ghadirian, A. M., Nair, N. P. V. and Schwartz, G. (1989). Effect of lithium and neuroleptic combination on lithium transport, blood pressure, and weight in bipolar patients. Biol. Psychiat., 26, 139–144PubMedCrossRefGoogle Scholar
  51. Goodnick, P. J. and Gershon, S. (1985). Lithium. In Handbook of Neurochemistry, 2nd edn, Vol. 9 (ed. A. Lajtha). Plenum Press, New York, pp. 103–149Google Scholar
  52. Green, H., Greenberg, S. M., Erickson, R. W., Sawyer, J. L. and Ellison, T. (1962). Effect of dietary phenylalanine and tryptophan upon rat brain amine levels. J. Pharmacol. Exp. Ther., 136, 174–178PubMedGoogle Scholar
  53. Green, A. R., Koslow, S. H. and Costa, E. (1973). Identification and quantitation of a new indolealkylamine in rat hypothalamus. Brain Res., 51, 371–374PubMedCrossRefGoogle Scholar
  54. Green, J. P. (1989). Histamine and serotonin. In Basic Neurochemistry (ed. G. Siegel, B. Agranoff, R. W. Albers and P. Molinoft). Raven Press, New York, pp. 253–269Google Scholar
  55. Haggendal, C. J. and Dählström, A. B. (1969). The transport and life-span of amine storage granules in bulbospinal noradrenaline neurons of the rat. J. Pharm. Pharmacol., 21, 55–57PubMedCrossRefGoogle Scholar
  56. Hamon, M., Bourgoin, S., Artaud, F. and Glowinski, J. (1979). The role of intraneuronal 5-HT and of tryptophan hydroxylase activation in the control of 5-HT synthesis in rat brain slices incubated in K+-enriched medium. J. Neurochem., 33, 1031–1042.PubMedCrossRefGoogle Scholar
  57. Hamon, M., Bourgoin, S., and Glowinski, J. (1973). Feedback regulation of 5-HT synthesis in rat striatal slices. J. Neurochem., 20, 1727–1745PubMedCrossRefGoogle Scholar
  58. Hoffman, E. J. and Phelps, M. E. (1986). Positron emission tomography: Principles and quantitation. In Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Health (ed. M. E. Phelps, J. C. Mazziotta and H. R. Shelbert). Raven Press, New York, pp. 237–286Google Scholar
  59. Johnston, J. P. (1968). Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem. Pharmacol., 17, 1285–1297PubMedCrossRefGoogle Scholar
  60. Jones, B.E., Halaris, A. E., McUhany, M. and Moore, R. Y. (1977). Ascending projections of the locus coeruleus in the rat. 1. Axonal transport in central noradrenaline neurons. Brain Res., 127, 1–21PubMedCrossRefGoogle Scholar
  61. Jouvet, M. (1967). Neurophysiology of the states of sleep. Physiol. Rev., 47, 117–177PubMedGoogle Scholar
  62. Kato, A., Diksic, M., Yamamoto, Y. L., Strother, S. C. and Feindel, W. (1984a). An improved approach for measurement of regional cerebral rate constants in the deoxyglucose method. J. Cereb. Blood Flow Metab., 4, 555–560PubMedCrossRefGoogle Scholar
  63. Kato, A., Menon, D., Diksic, M. and Yamamoto, Y. L. (1984b). Influence of the input function on the calculation of LCMRglu in the deoxyglucose model. J. Cereb. Blood Flow Metab., 4, 41–46PubMedCrossRefGoogle Scholar
  64. Katz, I. R. (1980). Oxygen affinity of tyrosine and tryptophan hydroxylases in synaptosomes. J. Neurochem., 35, 760–763PubMedCrossRefGoogle Scholar
  65. Kelder, D., Fagervall, I., Fowler, C. J. and Ross, S. B. (1989). Regulation of the monoamine concentrations in the rat brain by intraneuronal monoamine oxidase. Biogenic Amines, 6, 1–14Google Scholar
  66. Kirchgessner, A. L., Gershon, M. D., Liu, K. P. and Tamir, H. (1988). Co-storage of serotonin binding protein with serotonin in the rat CNS. J. Neurosci., 8, 3879–3890PubMedGoogle Scholar
  67. Kirikae, M., Diksic, M. and Yamamoto, Y. L. (1989). Quantitative measurements of regional glucose utilization and rate of valine incorporation into proteins by double-tracer autoradiography in the rat brain tumor model. J. Cereb. Blood Flow Metab., 9, 87–95PubMedCrossRefGoogle Scholar
  68. Kleven, M. S., Dwoskin, L. P. and Sparber, S. B. (1983). Pharmacological evidence for the existence of multiple functional pools of brain serotonin: analysis of brain perfusate from conscious rats. J. Neurochem., 41, 1143–1149PubMedCrossRefGoogle Scholar
  69. Knapp, S. and Mandell, A. J. (1972). Narcotic drugs: effects on the serotonin biosynthetic systems of the brain. Science, N. Y., 177, 1209–1211CrossRefGoogle Scholar
  70. Koe, B. K. and Weissmann, A. (1966). p-Chlorophenylalanine: a specific depleter of brain serotonin. J. Pharmacol. Exp. Ther., 154, 499–516PubMedGoogle Scholar
  71. Kopin, I.J. (1959). Tryptophan loading and excretion of 5-hydroxyindolacetic acid in normal and schizophrenic subjects. Science, N.Y., 129, 835–836CrossRefGoogle Scholar
  72. Korf, J. (1985). Turnover rate assessments of cerebral neurotransmitter amines and acetylcholine. In Neuromethods, Amines and their Metabolites (ed. A. A. Boulton, G. B. Baker and J. M. Baker). Humana Press, Clifton, NJ, pp. 407–456CrossRefGoogle Scholar
  73. Kuhar, M. J., Aghajanian, G. H. and Roth, R. H. (1972). Tryptophan hydroxylase activity and synaptosomal uptake of serotonin in discrete brain regions after midbrain raphe lesions: correlations with serotonin levels and histochemical fluorescence. Brain Res., 44, 165–176PubMedCrossRefGoogle Scholar
  74. Kuwabara, H., Evans, A. C. and Gjedde, A. (1990). Michaelis-Menten constraints improved cerebral glucose metabolism and regional lumped constant measurements with [18F]fluorodeoxyglucose. J. Cereb. Blood Flow Metab., 10, 180–189PubMedCrossRefGoogle Scholar
  75. Lane, J. D. and Aprison, M. H. (1978). The flux of radioactive label through compartments of the serotonergic system following the injection of [3H]tryptophan: product-precursor anomalies providing evidence that serotonin exists in multiple pools. J. Neurochem., 30, 671–678PubMedCrossRefGoogle Scholar
  76. McMillen, B. A., German, D. C. and Shore, P. A. (1980). Functional and pharmacological significance of brain dopamine and norepinephrine storage pools. Biochem. Pharmacol., 29, 3045–3050PubMedCrossRefGoogle Scholar
  77. Macon, J. B., Sokoloff, L. and Glowinski, J. (1971). Feedback control of rat brain 5-hydroxytryptamine synthesis. J. Neurochem., 18, 323–331PubMedCrossRefGoogle Scholar
  78. Madras, B. K. and Sourkes, T. L. (1965). Metabolism of α-methyl-tryptophan. Biochem. Pharmacol., 14, 1499–1506PubMedCrossRefGoogle Scholar
  79. Mandell, A. J. and Knapp, S. (1977). Regulation of serotonin biosynthesis in brain: role of the high affinity uptake of tryptophan into serotonergic neurons. Fed. Proc., 36, 2142–2148PubMedGoogle Scholar
  80. Mandell, A. J. and Knapp, S. (1979). Asymmetry and mood, emergent properties of serotonin regulation. Arch. Gen. Psychiat., 36, 909–916PubMedCrossRefGoogle Scholar
  81. Michaelis, L. and Menten, M. L. (1913). Die Kinetik der Invertinwirking. Biochem. Z., 49, 333–369Google Scholar
  82. Miller, L. P., Pardridge, W. M., Braun, L. D. and Oldendorf, W. H. (1985). Kinetic constants for blood-brain barrier amino acid transport in conscious rats. J. Neurochem., 45, 1427–1432PubMedCrossRefGoogle Scholar
  83. Missala, K. and Sourkes, T. L. (1988). Functional cerebral activity of an analogue of serotonin formed in situ. Neurochem. Int., 12, 209–214PubMedCrossRefGoogle Scholar
  84. Miwa, S., Fujiwara, M., Lee, K. and Fujiwara, M. (1987). Determination of serotonin turnover in the rat brain using 6-fluorotryptophan. J. Neurochem., 48, 1577–1580PubMedCrossRefGoogle Scholar
  85. Moir, A. T. B. (1974). Tryptophan concentration in brain. In Aromatic Amino Acids in the Brain (Ciba Foundation Symposium 22). Elsevier, Amsterdam, pp. 195–206Google Scholar
  86. Montine, T. J. and Sourkes, T. L. (1989). Behavior of alpha-methylserotonin in rat brain synaptosomes. Neurochem. Int., 15, 227–231PubMedCrossRefGoogle Scholar
  87. Moore, R. Y., Halaris, A. E. and Jones, B. E. (1987). Serotonin neurons of the midbrain raphe: ascending projections. J. Comp. Neurol., 80, 417–438Google Scholar
  88. Nagahiro, S., Diksic, M., Yamamoto, Y. L. and Riml, H. (1990a). Non-invasive in vivo autoradiographic method to measure axonal transport in serotoninergic neurons in the rat brain. Brain Res., 506, 120–128PubMedCrossRefGoogle Scholar
  89. Nagahiro, S., Takada, A., Diksic, M., Sourkes, T. L., Missala, K. and Yamamoto, Y. L. (1990b). A new method to measure brain serotonin synthesis in vivo. II. A practical autoradiographic method tested in normal and lithium-treated rats. J. Cereb. Blood Flow Metab., 10, 13–21PubMedCrossRefGoogle Scholar
  90. Neckers, L. M. (1982). Serotonin turnover and regulation. In Biology of Serotonergic Transmission (ed. N. N. Osborne). Wiley, New York, pp. 139–158Google Scholar
  91. Neff, N. H., Spano, P. F., Groppetti, A., Wang, C. T. and Costa, E. (1971). A simple procedure for calculating the synthesis rate of norepinephrine, dopamine and serotonin in rat brain. J. Pharmacol. Exp. Ther., 176, 701–710PubMedGoogle Scholar
  92. Neff, N. H. and Tozer, T. N. (1968). In vivo measurement of brain serotonin turnover. Adv. Pharmacol, 6A, 97–109CrossRefGoogle Scholar
  93. Neff, N. H., Tozer, T. N. and Brodie, B. B. (1967). Application of steady-state kinetics to studies of the transfer of 5-hydroxyindolacetic acid from brain to plasma. J. Pharmacol. Exp. Ther., 158, 214–218Google Scholar
  94. Nelson, T., Dienel, G. A., Mori, K., Cruz, N. F. and Sokoloff, L. (1987). Deoxyglucose-6-phosphate stability in vivo and deoxyglucose method: response to comments of Hawkins and Miller. J. Neurochem., 49, 1949–1960CrossRefGoogle Scholar
  95. Ng, L. K. Y., Chase, T. N., Colburn, R. W. and Kopin, I. J. (1972). Release of 3H-dopamine by L-5-hydroxytryptophan. Brain Res., 45, 499–505PubMedCrossRefGoogle Scholar
  96. Oldendorf, W. H. (1971). Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am. J. Physiol., 221, 1629–1639PubMedGoogle Scholar
  97. Oldendorf, W. H. and Szabo, J. (1976). Amino acid assignment to one of three blood-brain barrier acid carriers. Am. J. Physiol., 230, 94–98PubMedGoogle Scholar
  98. Osborne, N. N. (ed.) (1982). Biology of Serotonergic Transmission. Wiley, New YorkGoogle Scholar
  99. Palkovits, M., Brownstein, M., Kizer, J. S., Saavedra, J. M. and Kopin, I. J. (1976). Effect of stress on serotonin and tryptophan hydroxylase activity of brain nuclei. In Catecholamines and Stress (ed. E. Usdin et al.). Pergamon Press, Oxford, pp. 51–59Google Scholar
  100. Pardridge, W. M. (1977). Kinetics of competitive inhibition of neutral amino acid transport across the blood-brain barrier. J. Neurochem., 28, 103–108PubMedCrossRefGoogle Scholar
  101. Pardridge, W. M. and Mietus, L. J. (1982). Kinetics of neutral amino acid transport through the blood-brain barrier of the newborn rabbit. J. Neurochem., 38, 955–962PubMedCrossRefGoogle Scholar
  102. Patlak, S. C, Blasberg, R.G. and Fenstermacher, J. D. (1983). Graphic evaluation of blood-to-brain transfer constants from multiple time uptake data. J. Cereb. Blood Flow Metab., 3, 1–9PubMedCrossRefGoogle Scholar
  103. Perez-Cruet, J., Tagliamonte, A., Tagliamonte, P. and Gessa, G. L. (1971). Stimulation of serotonin synthesis by lithium. J. Pharmacol. Exp. Ther., 178, 325–330PubMedGoogle Scholar
  104. Petersen, S. L., Hartman, R. D. and Barraclough, C. A. (1989). An analysis of serotonin secretion in hypothalamic regions based on 5-hydroxytryptophan accumulation or push-pull perfusion. Effects of mesencephalic raphe on locus coeruleus stimulation and correlated changes in plasma luteinizing hormone. Brain Res., 495, 9–19, and references thereinPubMedCrossRefGoogle Scholar
  105. Phelps, M. E., Huang, S. C., Hoffman, E. J., Selin, M. S., Sokoloff, L. and Kuhl, D. E. (1979). Tomographic measurement of local cerebral glucose metabolic rate in humans with 2[18F]fluoro-2-deoxyglucose: validation of the method. Ann. Neurol., 6, 371–388PubMedCrossRefGoogle Scholar
  106. Philips, S. R., Durden, D. A. and Boulton, A. A. (1974). Identification and distribution of tryptamine in the rat. Can. J. Biochem., 52, 447–451PubMedCrossRefGoogle Scholar
  107. Redies, C. and Diksic, M. (1989). The deoxyglucose method in the ferret brain. I. Methodological considerations. J. Cereb. Blood Flow Metab., 9, 35–42PubMedCrossRefGoogle Scholar
  108. Redies, C, Diksic, M., Collier, B., Gjedde, A., Thompson, C. J., Gauthier, S. and Feindel, W. H. (1989). Influx of a choline analog to dog brain measured by positron emission tomography. Synapse, 2, 406–411CrossRefGoogle Scholar
  109. Ritger, P. D. and Rose, N. J. (1968). In Differential Equations with Applications. McGraw-Hill, New York, pp. 224–3Google Scholar
  110. Roberge, A. G., Missala, K. and Sourkes, T. L. (1972). Alpha-methyltryptophan: Effects on synthesis and degradation of serotonin in the brain. Neuropharmacology, 11, 197–209PubMedCrossRefGoogle Scholar
  111. Sako, K., Diksic, M., Kato, A., Yamamoto, Y. L. and Feindel, W. (1984). Evaluation of [18F]4-fluoroantipyrine as a new blood flow tracer for multinuclide autoradiography. J. Cereb. Blood Flow Metab., 4, 259–263PubMedCrossRefGoogle Scholar
  112. Sarna, G. S., Kantamaneni, B. D. and Curzon, G. (1985). Variables influencing the effect of a meal on brain tryptophan. J. Neurochem., 44, 1575–1580PubMedCrossRefGoogle Scholar
  113. Schirlin, D., Gerhart, F., Hornsperger, J. M., Hamon, M., Wagner, J. and Jung, M. J. (1988). Synthesis and biological properties of α-mono-and α-difluoromethyl derivatives of tryptophan and 5-hydroxytryptophan. J. Med. Chem., 31, 30–36PubMedCrossRefGoogle Scholar
  114. Schubert, J. (1974). Labelled 5-hydroxytryptamine and 5-hydroxyindolacetic acid formed in vivo from 3H-tryptophan in rat brain: effect of probenecid. Acta Physiol. Scand., 9, 401–408CrossRefGoogle Scholar
  115. Schute, H. H. (1976). Het Métabolisme van Serotonine in Rattehersenen. Thesis, University of GroningenGoogle Scholar
  116. Sedvall, G. (1981). Serotonin metabolite concentrations in cerebrospinal fluid from schizophrenic patients—relationships to family history. In Serotonin Current Aspects and Neurochemistry and function (ed. B. Haber, S. Gabay, M. R. Issidorides and S. G. A. Alivisatos). Plenum Press, New York, pp. 719–725, and references thereinGoogle Scholar
  117. Sharp, T., Bramwell, S. R., Clark, D. and Grahame-Smith, D. G. (1989). In vivo measurement of extracellular 5-hydroxytryptamine in hippocampus of the anesthetized rat using microdialysis: changes in relation to 5-hydroxytryptaminergic neuronal activity. J. Neurochem., 53, 234–240, and references thereinPubMedCrossRefGoogle Scholar
  118. Sheppard, C. W. (1948). The theory of the study of transfers within a multicompartment system using isotopic tracers. J. Appl. Phys., 19, 70–76CrossRefGoogle Scholar
  119. Shields, P. J. and Eccleston, D. (1972). Effects of electrical stimulation of rat midbrain on 5-hydroxytryptamine synthesis as determined by a sensitive radioisotope method. J. Neurochem., 19, 265–272PubMedCrossRefGoogle Scholar
  120. Smith, Q. R., Momma, S., Aoyagi, M. and Rappaport, Sl. (1987). Kinetics of neutral amino acid transport across the blood-brain barrier. J. Neurochem., 49, 1651–1658PubMedCrossRefGoogle Scholar
  121. Sokoloff, L., Reivich, M., Kennedy, C, Des Rosiers, M. H., Patlak, C. S., Pettigrew, K. D., Sakurada, O. and Shinohard, M. (1977). The 14C-deoxyglucose method for the measurement of local glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem., 28, 897–916.PubMedCrossRefGoogle Scholar
  122. Sourkes, T. L. (1971). Alpha-methyltryptophan and its action on tryptophan metabolism. Fed. Proc, 30, 897–903PubMedGoogle Scholar
  123. Steinbush, H. W. M., Verhofstad, A. A. J. and Joosten, W. J. (1978). Localization of serotonin in the central nervous system by immunohistochemistry: description of a specific and sensitive technique and some applications. Neuroscience, 3, 811–819CrossRefGoogle Scholar
  124. Stewart, P. M., Atherdel, S. M., Stewart, S. E., Whalley, L., Edwards, C. R. W. and Padfield, P. L. (1988). Lithium carbonate—a competitive aldosterone antagonist? Br. J. Psychiat., 153, 205–207CrossRefGoogle Scholar
  125. Susilo, R., Rommelspacher, H. and Höfle, G. (1989). Formation of thiazoüdine-4-carboxylic acid represents a main metabolic pathway of 5-hydroxytryptamine in rat brain. J. Neurochem., 52, 1793–1800PubMedCrossRefGoogle Scholar
  126. Sze, P. Y. (1981). Developmental-regulatory aspects of brain tryptophan hydroxylase. In Serotonin Current Aspects and Neurochemistry and Function (ed. B. Haber, S. Gabay, M. R. Issidorides and S. G. A. Alivisatos). Plenum Press, New York, pp. 507–523Google Scholar
  127. Tagaki, H., Shiosaka, S., Tohyama, M., Senba, E. and Sakanaka, M. (1980). Ascending components of the medial forebrain bundle from the lower brain stem in the rat, with special reference to raphe and catecholamine cell groups. Brain Res., 193, 315–337CrossRefGoogle Scholar
  128. Tamir, H., Klein, A. and Rapport, M. M. (1976). Serotonin binding protein: Enhancement of binding by Fe2+ and inhibition of binding by drugs. J. Neurochem., 26, 871–878PubMedCrossRefGoogle Scholar
  129. Tappaz, M. and Pujol, J.-F. (1980). Estimation of the rate of tryptophan hydroxylation in vivo: A sensitive microassay in discrete rat brain nuclei. J. Neurochem., 34, 933–940PubMedCrossRefGoogle Scholar
  130. Teorell, T. (1937). Kinetics of distribution of substances administered to the body. I. Extravascular modes of administration. Arch. Int. Pharmacodyn., 57, 205–240Google Scholar
  131. Tozer, T. N., Neff, N. H. and Brodie, B. B. (1966). Application of steady-state kinetics to the synthesis rate and turnover time of serotonin in the brain of normal and reserpine-treated rats. J. Pharmacol. Exp. Ther., 153, 177–182Google Scholar
  132. Tracqui, P., Brézillon, P., Staub, J. F., Morot-Gaudry, Y., Hamon, M. and Perault-Staub, A. M. (1983a). Model of brain serotonin metabolism. I. Structure determination-parameter estimation. Am. J. Physiol., 244, R193-R205Google Scholar
  133. Tracqui, P., Morot-Gaudry, Y., Staub, J. F., Brézillon, P., Perault-Staub, A. M., Burgoin, S. and Hamon, M. (1983b). Model of brain serotonin metabolism. II. Physiological interpretation. Am. J. Physiol., 244, R206-R215Google Scholar
  134. van Wijk, M. and Korf, J. (1981). Postmortem changes of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in mouse brain and their prevention by pargyline and microwave irradiation. Neurochem. Res., 6, 425–430PubMedCrossRefGoogle Scholar
  135. van Wijk, M., Sebens, J. B. and Korf, J. (1979). Probenecid-induced increase of 5-hydroxytryptamine synthesis in rat brain as measured by formation of 5-hydroxytryptophan. Psychopharmacology, 60, 229–235PubMedCrossRefGoogle Scholar
  136. Weissman, D., Belin, M. F., Aguera, M., Meunière, C., Maitre, M., Cash, C. D., Ehret, M., Pandel, P. and Pujol, J. F. (1987). Immunohistochemistry of tryptophan hydroxylase in the rat brain. Neuroscience, 23, 291–304CrossRefGoogle Scholar
  137. Yamamoto, Y. L., Thompson, C. J., Meyer, E., Robertson, J. and Feindel, W. L. (1977). Dynamic positron emission tomography for study of cerebral haemodynamics in a cross-section of the head using positron emitting 68Ga-EDTA and Kr77.J. Comp. Assist. Tomogr., 1, 43–56CrossRefGoogle Scholar
  138. Young, S. N., Chouinard, G. and Annable, A. (1981). Tryptophan in treatment of depression. In Serotonin Current Aspects and Neurochemistry and function (ed. B. Haber, S. Gabay, M. R. Issidorides and S. G. A. Alivisatos). Plenum Press, New York, pp. 727–737, and references thereinGoogle Scholar
  139. Young, S. N. and Sourkes, T. L. (1977). Tryptophan in the central nervous system: regulation and significance. Adv. Neurochem., 2, 133–191CrossRefGoogle Scholar
  140. Young, S. N. and Teff, K. L. (1989). Tryptophan availability, 5HT synthesis and 5HT function. Progr. Neuro-Psychopharmacol. Biol. Psychiatric., 13, 373–379CrossRefGoogle Scholar
  141. Yudilevich, D. L., DeRose, N. and Sepulveda, F. V. (1972). Facilitated transport of amino acids through the blood-brain barrier of the dog studied in a single capillary circulation. Brain Res., 44, 569–578PubMedCrossRefGoogle Scholar

Copyright information

© Macmillan Publishers Limited 1991

Authors and Affiliations

  • Mirko Diksic
    • 1
    • 2
  1. 1.Department of Neurology and NeurosurgeryMcGill UniversityMontrealCanada
  2. 2.Montreal Neurological Institute and HospitalCanada

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