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. 1992 Jan;105(1):59–62. doi: 10.1111/j.1476-5381.1992.tb14210.x

Effect of milacemide on extracellular and tissue concentrations of dopamine and 5-hydroxytryptamine in rat frontal cortex.

J Semba 1, M Doheny 1, P N Patsalos 1, G Sarna 1, G Curzon 1
PMCID: PMC1908633  PMID: 1596690

Abstract

1. Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2. Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400 mg kg-1, i.p.), peaking at 1 h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-1 milacemide). 3. Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400 mg kg-1. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4. Milacemide (400 mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5. The results are explicable in terms of an inhibition by milacemide of MAO-A.

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Selected References

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  1. Adell A., Sarna G. S., Hutson P. H., Curzon G. An in vivo dialysis and behavioural study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats. Br J Pharmacol. 1989 May;97(1):206–212. doi: 10.1111/j.1476-5381.1989.tb11943.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bannon M. J., Roth R. H. Pharmacology of mesocortical dopamine neurons. Pharmacol Rev. 1983 Mar;35(1):53–68. [PubMed] [Google Scholar]
  3. Brown P., Thompson P. D., Rothwell J. C., Day B. L., Marsden C. D. A therapeutic trial of milacemide in myoclonus and the stiff-person syndrome. Mov Disord. 1991;6(1):73–75. doi: 10.1002/mds.870060114. [DOI] [PubMed] [Google Scholar]
  4. Brozoski T. J., Brown R. M., Rosvold H. E., Goldman P. S. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science. 1979 Aug 31;205(4409):929–932. doi: 10.1126/science.112679. [DOI] [PubMed] [Google Scholar]
  5. Butcher S. P., Fairbrother I. S., Kelly J. S., Arbuthnott G. W. Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J Neurochem. 1990 Sep;55(3):981–988. doi: 10.1111/j.1471-4159.1990.tb04587.x. [DOI] [PubMed] [Google Scholar]
  6. Chadwick D., Hallett M., Harris R., Jenner P., Reynolds E. H., Marsden C. D. Clinical, biochemical, and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibitor, and clonazepam. Brain. 1977 Sep;100(3):455–487. doi: 10.1093/brain/100.3.455. [DOI] [PubMed] [Google Scholar]
  7. Christophe J., Kutzner R., Nguyen-Bui N. D., Damien C., Chatelain P., Gillet L. Conversion of orally administered 2-n.pentylaminoacetamide into glycinamide and glycine in the rat brain. Life Sci. 1983 Aug 8;33(6):533–541. doi: 10.1016/0024-3205(83)90127-3. [DOI] [PubMed] [Google Scholar]
  8. Elchisak M. A., Cosgrove S. E., Ebert M. H., Burns R. S. Distribution of free and conjugated dopamine in monkey brain, peripheral tissues and cerebrospinal fluid determined by high-performance liquid chromatography. Brain Res. 1983 Nov 21;279(1-2):171–176. doi: 10.1016/0006-8993(83)90175-0. [DOI] [PubMed] [Google Scholar]
  9. Elchisak M. A., Maas J. W., Roth R. H. Dihydroxyphenylacetic acid conjugate: natural occurrence and demonstration of probenecid-induced accumulation in rat striatum, olfactory tubercles and frontal cortex. Eur J Pharmacol. 1977 Feb 21;41(4):369–378. doi: 10.1016/0014-2999(77)90257-6. [DOI] [PubMed] [Google Scholar]
  10. Fowler C. J., Benedetti M. S. The metabolism of dopamine by both forms of monoamine oxidase in the rat brain and its inhibition by cimoxatone. J Neurochem. 1983 Jun;40(6):1534–1541. doi: 10.1111/j.1471-4159.1983.tb08123.x. [DOI] [PubMed] [Google Scholar]
  11. Garrett M. C., Soares-da-Silva P. Role of type A and B monoamine oxidase on the formation of 3,4-dihydroxyphenylacetic acid (DOPAC) in tissues from the brain of the rat. Neuropharmacology. 1990 Oct;29(10):875–879. doi: 10.1016/0028-3908(90)90136-f. [DOI] [PubMed] [Google Scholar]
  12. Godfraind J. M. Microionophoretic study with milacemide, a glycine precursor, on mammalian central nervous system cells. Br J Pharmacol. 1990 May;100(1):119–125. doi: 10.1111/j.1476-5381.1990.tb12062.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Green A. R., Mitchell B. D., Tordoff A. F., Youdim M. B. Evidence for dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of inhibition of enzyme necessary for increased functional activity of dopamine and 5-hydroxytryptamine. Br J Pharmacol. 1977 Jul;60(3):343–349. doi: 10.1111/j.1476-5381.1977.tb07506.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Handelmann G. E., Nevins M. E., Mueller L. L., Arnolde S. M., Cordi A. A. Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents. Pharmacol Biochem Behav. 1989 Dec;34(4):823–828. doi: 10.1016/0091-3057(89)90281-5. [DOI] [PubMed] [Google Scholar]
  15. Houtkooper M. A., van Oorschot C. A., Rentmeester T. W., Höppener P. J., Onkelinx C. Double-blind study of milacemide in hospitalized therapy-resistant patients with epilepsy. Epilepsia. 1986 May-Jun;27(3):255–262. doi: 10.1111/j.1528-1157.1986.tb03537.x. [DOI] [PubMed] [Google Scholar]
  16. Hutson P. H., Curzon G. Concurrent determination of effects of p-chloroamphetamine on central extracellular 5-hydroxytryptamine concentration and behaviour. Br J Pharmacol. 1989 Apr;96(4):801–806. doi: 10.1111/j.1476-5381.1989.tb11887.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hutson P. H., Sarna G. S., Kantamaneni B. D., Curzon G. Monitoring the effect of a tryptophan load on brain indole metabolism in freely moving rats by simultaneous cerebrospinal fluid sampling and brain dialysis. J Neurochem. 1985 Apr;44(4):1266–1273. doi: 10.1111/j.1471-4159.1985.tb08753.x. [DOI] [PubMed] [Google Scholar]
  18. Hwang E. C., Van Woert M. H. p,p'-DDT-induced neurotoxic syndrome: experimental myoclonus. Neurology. 1978 Oct;28(10):1020–1025. doi: 10.1212/wnl.28.10.1020. [DOI] [PubMed] [Google Scholar]
  19. Janssens de Varebeke P., Cavalier R., David-Remacle M., Youdim M. B. Formation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase B. J Neurochem. 1988 Apr;50(4):1011–1016. doi: 10.1111/j.1471-4159.1988.tb10566.x. [DOI] [PubMed] [Google Scholar]
  20. Janssens de Varebeke P., Pauwels G., Buyse C., David-Remacle M., De Mey J., Roba J., Youdim M. B. The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monoamine oxidase B. J Neurochem. 1989 Oct;53(4):1109–1116. doi: 10.1111/j.1471-4159.1989.tb07403.x. [DOI] [PubMed] [Google Scholar]
  21. Kato T., Dong B., Ishii K., Kinemuchi H. Brain dialysis: in vivo metabolism of dopamine and serotonin by monoamine oxidase A but not B in the striatum of unrestrained rats. J Neurochem. 1986 Apr;46(4):1277–1282. doi: 10.1111/j.1471-4159.1986.tb00650.x. [DOI] [PubMed] [Google Scholar]
  22. Pratt J. A., Rothwell J., Jenner P., Marsden C. D. Myoclonus in the rat induced by p,p'-DDT and the role of altered monoamine function. Neuropharmacology. 1985 May;24(5):361–373. doi: 10.1016/0028-3908(85)90020-6. [DOI] [PubMed] [Google Scholar]
  23. Saletu B., Grünberger J., Linzmayer L. Acute and subacute CNS effects of milacemide in elderly people: double-blind, placebo-controlled quantitative EEG and psychometric investigations. Arch Gerontol Geriatr. 1986 Oct;5(3):165–181. doi: 10.1016/0167-4943(86)90019-1. [DOI] [PubMed] [Google Scholar]
  24. Sarna G. S., Hutson P. H., Curzon G. Effect of alpha-methyl fluorodopa on dopamine metabolites: importance of conjugation and egress. Eur J Pharmacol. 1984 May 4;100(3-4):343–350. doi: 10.1016/0014-2999(84)90011-6. [DOI] [PubMed] [Google Scholar]
  25. Scatton B., Javoy-Agid F., Rouquier L., Dubois B., Agid Y. Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease. Brain Res. 1983 Sep 26;275(2):321–328. doi: 10.1016/0006-8993(83)90993-9. [DOI] [PubMed] [Google Scholar]
  26. Schwartz D. H., Hernandez L., Hoebel B. G. Serotonin release in lateral and medial hypothalamus during feeding and its anticipation. Brain Res Bull. 1990 Dec;25(6):797–802. doi: 10.1016/0361-9230(90)90173-w. [DOI] [PubMed] [Google Scholar]
  27. Semba J., Ratnaraj N., Patsalos P. N. Simple and rapid micro-analytical procedures for the estimation of milacemide and its metabolite glycinamide in rat plasma and cerebrospinal fluid by high-performance liquid chromatography. J Chromatogr. 1991 Apr 19;565(1-2):357–362. doi: 10.1016/0378-4347(91)80396-t. [DOI] [PubMed] [Google Scholar]
  28. Simon H., Scatton B., Moal M. L. Dopaminergic A10 neurones are involved in cognitive functions. Nature. 1980 Jul 10;286(5769):150–151. doi: 10.1038/286150a0. [DOI] [PubMed] [Google Scholar]
  29. Sleight A. J., Marsden C. A., Martin K. F., Palfreyman M. G. Relationship between extracellular 5-hydroxytryptamine and behaviour following monoamine oxidase inhibition and L-tryptophan. Br J Pharmacol. 1988 Feb;93(2):303–310. doi: 10.1111/j.1476-5381.1988.tb11435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Truong D. D., Diamond B., Pezzoli G., Mena M. A., Fahn S. Monoamine oxidase inhibitory properties of milacemide in rats. Life Sci. 1989;44(15):1059–1066. doi: 10.1016/0024-3205(89)90558-4. [DOI] [PubMed] [Google Scholar]
  31. Truong D. D., Galloway M. P., Pezzoli G., Jamrozik Z., Fahn S. Milacemide increases 5-hydroxytryptamine and dopamine levels in rat brain--possible mechanisms of milacemide antimyoclonic property in the p,p'-DDT-induced myoclonus. Pharmacol Biochem Behav. 1989 Apr;32(4):993–1001. doi: 10.1016/0091-3057(89)90072-5. [DOI] [PubMed] [Google Scholar]
  32. Truong D. D., Garcia De Yebenes J., Pezzoli G., Jackson-Lewis V., Fahn S. Glycine involvement in DDT-induced myoclonus. Mov Disord. 1988;3(1):77–87. doi: 10.1002/mds.870030110. [DOI] [PubMed] [Google Scholar]
  33. Waldmeier P. C. Amine oxidases and their endogenous substrates (with special reference to monoamine oxidase and the brain). J Neural Transm Suppl. 1987;23:55–72. doi: 10.1007/978-3-7091-8901-6_4. [DOI] [PubMed] [Google Scholar]
  34. Westerink B. H., Damsma G., Rollema H., De Vries J. B., Horn A. S. Scope and limitations of in vivo brain dialysis: a comparison of its application to various neurotransmitter systems. Life Sci. 1987 Oct 12;41(15):1763–1776. doi: 10.1016/0024-3205(87)90695-3. [DOI] [PubMed] [Google Scholar]
  35. de Boer P., Damsma G., Fibiger H. C., Timmerman W., de Vries J. B., Westerink B. H. Dopaminergic-cholinergic interactions in the striatum: the critical significance of calcium concentrations in brain microdialysis. Naunyn Schmiedebergs Arch Pharmacol. 1990 Nov;342(5):528–534. doi: 10.1007/BF00169041. [DOI] [PubMed] [Google Scholar]
  36. de Varebeke P. J., Niebes P., Pauwels G., Roba J., Korf J. Effect of milacemide, a glycinamide derivative, on the rat brain gamma-aminobutyric acid system. Biochem Pharmacol. 1983 Sep 15;32(18):2751–2755. doi: 10.1016/0006-2952(83)90087-4. [DOI] [PubMed] [Google Scholar]
  37. van Dorsser W., Barris D., Cordi A., Roba J. Anticonvulsant activity of milacemide. Arch Int Pharmacodyn Ther. 1983 Dec;266(2):239–249. [PubMed] [Google Scholar]

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