Biological model for the in vivo measurement of rate of serotonin synthesis in the brain

  • M. Diksic
  • S. Nagahiro
  • T. L. Sourkes
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 29)


A biological model for the measurement of the rate of serotonin synthesis in rat brain with α-[14C]methyl-L-tryptophan is described. The rate of serotonin synthesis in several grossly dissected brain structures is reported. The half-life of the precursor pool, estimated from kinetic data, is between 20 and 25 min. The method allows, for the first time, measurement of the brain serotonin synthesis rate without any pharmacological manipulation and does not require separation of metabolites. Autoradiographic data are also presented to demonstrate anatomical resolution of this method. The synthesis rate can be estimated in a large number of discrete structures when autoradiography is applied. Long retention of the tracer in brain is also demonstrated.


Biological Model Dorsal Raphe Nucleus Cereb Blood Flow Pharmacological Manipulation Serotonin Synthesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Chaly T, Diksic M (1988) Synthesis of “no-carrier-added” alpha-[11C]methyl-L-trypto-phan. J Nucl Med 29: 370–374.PubMedGoogle Scholar
  2. Chaouloff F, Laude E, Mignot E, Kanoun P, Elghozi JL (1985) Tryptophan and serotonin turnover rate in the brain of genetically hyperammonemic mice. Neurochem Int 7: 143–153.PubMedCrossRefGoogle Scholar
  3. Curzon G, Joseph MH, Knott PJ (1972) Effects of immobilization and food deprivation on rat brain tryptophan metabolism. J Neurochem 19: 1967–1974.PubMedCrossRefGoogle Scholar
  4. Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL (1989) A new method to measure brain serotonin synthesis in vivo: I-theory and basic data for a biological model. J Cereb Blood Flow Metab (in press).Google Scholar
  5. Diksic M, Sourkes TL, Nagahiro H, Chaly T, Missala K (1988) Influence of plasma tryptophan and PaCO2 on brain serotonin synthesis in dog as measured with PET. J Nucl Med 29: 784.Google Scholar
  6. Diksic M, Sourkes TL, Nagahiro H, Chaly T, Missala K, Yamamoto YL (1987) In vivo rate of serotonin synthesis in the dog brain measured by positron emission tomography. Proc 17th Ann Meeting of Soc Neurosc, Abstr. No. 224.5.Google Scholar
  7. Evans AC, Diksic M, Yamamoto YL, Kato A, Dagher A, Redies C, 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: 724–738.PubMedCrossRefGoogle Scholar
  8. Forsythe GE, Malcolm MA, Moler CB (1977) Computer methods for mathematical computations. Prentice-Hall, Englewood Cliffs N J, pp 169–191.Google Scholar
  9. Gal EM, Christiansen PA (1975) Alpha-methyltryptophan: effect on cerebral monooxy-genases in vitro and in vivo. J Neurochem 24: 89–95.PubMedCrossRefGoogle Scholar
  10. Gjedde A (1982) Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: a re-examination. Brain Res Rev 4: 237–274.CrossRefGoogle Scholar
  11. Joseph MH, Kennett GA (1983) Stress-induced release of 5-HT in the hippocampus and its dependence on increased tryptophan availability: an in vivo electrochemical study. Brain Res 270: 251–257.PubMedCrossRefGoogle Scholar
  12. Kirikae M, Diksic M, Yamamoto YL (1989) Quantitative measurements of regional glucose utilization and rate of valine incorporation into proteins by double-tracer autoradiog-raphy in rat brain tumor model. J Cereb Blood Flow Metab 9: 87–95.PubMedCrossRefGoogle Scholar
  13. Korf J (1985) Turnover rate assessments of cerebral neurotransmitter amines and acetyl-choline. In: Boulton AA, Baker GB, Baker JM (eds) Neuromethods, vol 2. Amines and their metabolites. Humana Press, Clifton N J, pp 407–456, and references therein.Google Scholar
  14. Korf J, van Praag HM, Sebens JB (1972) Serum tryptophan decreased, brain tryptophan increased and brain serotonin synthesis unchanged after probenecid loading. Brain Res 42: 239–242.PubMedCrossRefGoogle Scholar
  15. Krstulovic AM, Matsura C (1979) Rapid analysis of tryptophan metabolites using reverse-phase high-performance chromatography with fluorometric detector. J Chromatogr 163: 72–76.PubMedCrossRefGoogle Scholar
  16. Long JB, Youngblood WY, Kizer JS (1983) Regional differences in the response of ser-otonergic neurons in rat CNS to drugs. Eur J Pharmacol 88: 89–97.PubMedCrossRefGoogle Scholar
  17. Lovenberg W, Jequier E, Sjoerdsma A (1967) Tryptophan hydroxylation: measurement in pineal gland, brain stem and carcinoid tumor. Science 155: 217–219.PubMedCrossRefGoogle Scholar
  18. Macon JB, Sokoloff L, Glowinski J (1971) Feed-back control of rat brain 5-hydroxytrypt-amine synthesis. J Neurochem 18: 323–331.PubMedCrossRefGoogle Scholar
  19. Madrass BK, Sourkes TL (1965) Metabolism of α-methyltryptophan. Biochem Pharmacol 14: 1499–1506.CrossRefGoogle Scholar
  20. Missala K, Sourkes TL (1988) Functional cerebral activity of an analogue of serotonin formed in situ. Neurochem Int 12: 209–214.PubMedCrossRefGoogle Scholar
  21. Miwa S, Fujiwara M, Lee K, Fujiwara M (1987) Determination of serotonin turnover in rat brain using 6-fluorotryptophan. J Neurochem 48: 1577–1580.PubMedCrossRefGoogle Scholar
  22. Moir ATB, Eccleston D (1968) The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 15: 1093–1108.PubMedCrossRefGoogle Scholar
  23. Nagahiro S, Takada A, Diksic M, Sourkes TL, Missala K, Yamamoto YL (1989) 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 (in press).Google Scholar
  24. Neckers LM, Meek JL (1976) Measurement of 5HT turnover rate in discrete nuclei of rat brain. Life Sci 19: 1579–1584.PubMedCrossRefGoogle Scholar
  25. Patlak SC, Blasberg RG, Fenstermacher JD (1983) Graphic evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3: 19.CrossRefGoogle Scholar
  26. Roberge AG, Missala K, Sourkes TL (1972) Alpha-methyltryptophan: effects on synthesis and degradation of serotonin in the brain. Neuropharmacology 11: 197–209.PubMedCrossRefGoogle Scholar
  27. Sako K, Diksic M, Kato A, Yamamoto YL, Feindel W (1984) Evaluation of 4-[18F]fluoroantipyrine as a new blood flow tracer for multiradionuclide autoradiog-raphy. J Cereb Blood Flow Metab 4: 259–263.PubMedCrossRefGoogle Scholar
  28. Sarna GS, Kantamaneni BD, Curzon G (1985) Variables influencing the effect of a meal on brain tryptophan. J Neurochem 44: 1575–1580.PubMedCrossRefGoogle Scholar
  29. Schirlin D, Gerhart F, Hornsperger JM, Hamon M, Wagner J, Jung MJ (1988) Synthesis and biological properties of alpha-mono-and alpha-difluoromethyl derivatives of tryptophan and 5-hydroxytryptophan. J Med Chem 31: 30–36.PubMedCrossRefGoogle Scholar
  30. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, 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
  31. Sourkes TL (1971) Alpha-methyltryptophan and its action on tryptophan metabolism. Fed Proc 30: 897–903.PubMedGoogle Scholar
  32. Tagliamonte A, Tagliamonte P, Perez-Cruet J, Stern S, Gessa GL (1971) Effect of psy-chotropic drugs on tryptophan concentration in the rat brain. J Pharmacol Exp Ther 177: 465–480.Google Scholar
  33. Tappaz M, Pujol J-F (1980) Estimation of the rate of tryptophan hydroxylation in vivo: a sensitive microassay in discrete rat brain nuclei. J Neurochem 34: 933–940.PubMedCrossRefGoogle Scholar
  34. Yuwiler A, Oldendorf WH, Geller E, Braun L (1977) Effect of albumin binding and amino acid competition of tryptophan uptake into brain. J Neurochem 28: 1015–1023.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • M. Diksic
    • 1
    • 3
  • S. Nagahiro
    • 1
  • T. L. Sourkes
    • 2
  1. 1.Montreal Neurological Institute and Hospital, and Department of Neurology and NeurosurgeryMcGill UniversityMontrealCanada
  2. 2.Departments of Psychiatry and BiochemistryMcGill UniversityMontrealCanada
  3. 3.Medical Cyclotron UnitMcGill UniversityMontrealCanada

Personalised recommendations