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. 1975 Nov;55(3):415–422. doi: 10.1111/j.1476-5381.1975.tb06946.x

Effects of monoamine oxidase inhibition by clorgyline, deprenil or tranylcypromine on 5-hydroxytryptamine concentrations in rat brain and hyperactivity following subsequent tryptophan administration.

A R Green, M B Youdim
PMCID: PMC1666694  PMID: 1203627

Abstract

1 The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5-hydroxytryptamine (5-HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5-HT was also examined both after tranylcypromine alone and also when L-tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine. 2 All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5-HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5-HT in vivo. When tryptophan was also given, there was a further rise of brain 5-HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made is appearance. 3 Clorgyline (a "Type A" MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5-HT oxidation by 100%. Deprenil (a "Type B" MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5-HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5-HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5-HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan. 4 Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5-HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5-HT nearly as great as that seen following tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive. 5 No evidence was found pointing to the formation of any other 5-substituted indole in the brain following tranylcypromine plus L-tryptophan administration as suggested by others. 6 It is concluded that while 5-HT may normally be metabolized in the brain by "Tye A" MAO in vivo, when this form is inhibited, 5-HT can still be metabolized by "Type B" enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5-HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.

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Selected References

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  1. CHANG C. C. A SENSITIVE METHOD FOR SPECTROPHOTOFLUOROMETRIC ASSAY OF CATECHOLAMINES. Int J Neuropharmacol. 1964 Dec;3:643–649. doi: 10.1016/0028-3908(64)90089-9. [DOI] [PubMed] [Google Scholar]
  2. Curzon G., Green A. R. Rapid method for the determination of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in small regions of rat brain. Br J Pharmacol. 1970 Jul;39(3):653–655. doi: 10.1111/j.1476-5381.1970.tb10373.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Denckla W. D., Dewey H. K. The determination of tryptophan in plasma, liver, and urine. J Lab Clin Med. 1967 Jan;69(1):160–169. [PubMed] [Google Scholar]
  4. Gascoigne J. E., Williams D., Williams E. D. Proceedings: Histochemical demonstration of an additional form of rat brain MAO. Br J Pharmacol. 1975 Jun;54(2):274P–274P. [PMC free article] [PubMed] [Google Scholar]
  5. Grahame-Smith D. G. Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J Neurochem. 1971 Jun;18(6):1053–1066. doi: 10.1111/j.1471-4159.1971.tb12034.x. [DOI] [PubMed] [Google Scholar]
  6. Green A. R., Grahame-Smith D. G. The role of brain dopamine in the hyperactivity syndrome produced by increased 5-hydroxytryptamine synthesis in rats. Neuropharmacology. 1974 Nov;13(10-11):949–959. doi: 10.1016/0028-3908(74)90086-0. [DOI] [PubMed] [Google Scholar]
  7. Green A. R., Hughes J. P., Tordoff A. F. The concentration of 5-methoxytryptamine in rat brain and its effects on behaviour following its peripheral injection. Neuropharmacology. 1975 Aug;14(8):601–606. doi: 10.1016/0028-3908(75)90127-6. [DOI] [PubMed] [Google Scholar]
  8. Green A. R., Koslow S. H., Costa E. Identification and quantitation of a new indolealkylamine in rat hypothalamus. Brain Res. 1973 Mar 15;51:371–374. doi: 10.1016/0006-8993(73)90392-2. [DOI] [PubMed] [Google Scholar]
  9. Green A. R., Sourkes T. L., Young S. N. Liver and brain tryptophan metabolism following hydrocortisone administration to rats and gerbils. Br J Pharmacol. 1975 Feb;53(2):287–292. doi: 10.1111/j.1476-5381.1975.tb07360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Green A. R., Woods H. F., Knott P. G., Curzon G. Letter: Factors influencing effect of hydrocortisone on rat brain tryptophan metabolism. Nature. 1975 May 8;255(5504):170–170. doi: 10.1038/255170a0. [DOI] [PubMed] [Google Scholar]
  11. Houslay M. D., Tipton K. F. A kinetic evaluation of monoamine oxidase activity in rat liver mitochondrial outer membranes. Biochem J. 1974 Jun;139(3):645–652. doi: 10.1042/bj1390645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Johnston J. P. Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol. 1968 Jul;17(7):1285–1297. doi: 10.1016/0006-2952(68)90066-x. [DOI] [PubMed] [Google Scholar]
  13. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  14. Neff N. H., Tozer T. N. In vivo measurement of brain serotonin turnover. Adv Pharmacol. 1968;6(Pt A):97–109. doi: 10.1016/s1054-3589(08)61160-6. [DOI] [PubMed] [Google Scholar]
  15. Sandler M., Youdim M. B. Monoamine oxidases: the present status. Int Pharmacopsychiatry. 1974;9(1):27–34. doi: 10.1159/000468113. [DOI] [PubMed] [Google Scholar]
  16. Sandler M., Youdim M. B. Multiple forms of monoamine oxidase: functional significance. Pharmacol Rev. 1972 Jun;24(2):331–348. [PubMed] [Google Scholar]
  17. Snyder S. H., Axelrod J., Zweig M. A sensitive and specific fluorescence assay for tissue serotonin. Biochem Pharmacol. 1965 May;14(5):831–835. doi: 10.1016/0006-2952(65)90102-4. [DOI] [PubMed] [Google Scholar]
  18. Southgate J., Collins G. G. The estimation of monoamine oxidase using 14C-labelled substrates. Biochem Pharmacol. 1969 Sep;18(9):2285–2287. doi: 10.1016/0006-2952(69)90341-4. [DOI] [PubMed] [Google Scholar]
  19. Squires R. F. Evidence that 5-methoxy-N, N-dimethyl tryptamine is a specific substrate for MAO-A in the rat: implications for the indoleamine dependent behavioural syndrome. J Neurochem. 1975 Jan;24(1):47–50. doi: 10.1111/j.1471-4159.1975.tb07626.x. [DOI] [PubMed] [Google Scholar]
  20. Squires R. F., Lassen J. B. The inhibition of A and B forms of MAO in the production of a characteristic behabioural syndrome in rats after 1-tryptophan loading. Psychopharmacologia. 1975;41(2):145–151. doi: 10.1007/BF00421072. [DOI] [PubMed] [Google Scholar]
  21. Yang H. Y., Neff N. H. The monoamine oxidases of brain: selective inhibition with drugs and the consequences for the metabolism of the biogenic amines. J Pharmacol Exp Ther. 1974 Jun;189(3):733–740. [PubMed] [Google Scholar]
  22. Youdim M. B., Collins G. G., Sandler M., Bevan Jones A. B., Pare C. M., Nicholson W. J. Human brain monoamine oxidase: multiple forms and selective inhibitors. Nature. 1972 Mar 31;236(5344):225–228. doi: 10.1038/236225b0. [DOI] [PubMed] [Google Scholar]
  23. Youdim M. B. Multiple forms of mitochondrial monoamine oxidase. Br Med Bull. 1973 May;29(2):120–122. doi: 10.1093/oxfordjournals.bmb.a070980. [DOI] [PubMed] [Google Scholar]

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