Summary
Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nervertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism underbasal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the “cheese effect” such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.
Similar content being viewed by others
References
Berry MD, Juorio AV, Paterson IA (1994a) The functional role of monoamine oxidases A and B in the mammalian central nervous system. Prog Neurobiol 42: 375–391
Berry MD, Juorio AV, Paterson IA (1994b) Possible mechanisms of action of (−)deprenyl and other MAO-B inhibitors in some neurological and psychiatric conditions. Prog Neurobiol 44: 141–161
Birkmayer W, Riederer P, Youdim MBH, Linauer W (1975) The potentiation of the antikinetic effect after L-dopa treatment by an inhibitor of MAO-B, deprenyl. J Neural Transm 36: 303–326
Birkmayer W, Knoll J, Riederer P, Youdim MBH (1983) (−)Deprenyl leads to prolongation of Ldopa efficacy in Parkinson's disease. Mod Probl Pharmacopsychiatry 19: 170–176
Brannan T, Martínez-Tica J, Yahr MD (1991) Effect of dietary protein on striatal dopamine formation following L-dopa administration: an in vivo study. Neuropharmacology 30: 1125–1127
Brannan T, Martínez-Tica J, Yahr MD (1992) Changes in body temperature markedly affect striatal dopamine release and metabolism: an in vivo study. J Neural Transm [Gen Sect] 89: 193–196
Brannan T, Prikhojan A, Yahr MD (1994) Effect of a selective MAO-A inhibitor (Ro 41-1049) on striatal L-dopa and dopamine metabolism: an in vivo study. J Neural Transm [PD Sect] 8: 99–105
Brannan T, Yahr MD (1995) Comparative study of selegiline plus L-dopa-carbidopa versus L-dopa-carbidopa alone in the treatment of Parkinson's disease. Ann Neurol 37: 95–98
Butcher SP, Fairbrother IS, Kelly JS, Arbuthnott GW (1990) Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J Neurochem 55: 981–988
Cesura AM, Pletscher A (1992) The new generation of monoamine oxidase inhibitors. Prog Drug Res 38: 171–297
Colzi A, d'Agostini F, Kettler R, Borroni E, Da Prada M (1990) Effect of selective and reversible MAO inhibitors on dopamine outflow in rat striatum: a microdialysis study. J Neural Transm [Suppl] 32: 79–84
Colzi A, d'Agostini AM, Da Prada M (1992) Brain microdialysis in rats: a technique to reveal competition in vivo between endogenous dopamine and moclobemide, a RIMA antidepressant. Psychopharmacol 106: S17-S20
Da Prada M, Kettler R, Keller HH, Cesura AM, Richards JG, Saura Marti J, Muggli-Maniglio D, Wyss PC, Kuburz E, Imhof R (1990) From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class or reversible, selective MAO-A and MAO-B inhibitors. J Neural Transm [Suppl] 29: 279–292
Di Chiari G, Carboni E, Morelli M, Cozzolino A, Tanda GL, Pinna A, Russi G, Consolo S (1993) Stimulation of dopamine transmission in the dorsal caudate nucleus by pargyline as demonstrated by dopamine and acetylcholine microdialysis and FOS immunochemistry. Neuroscience 55: 451–456
Haefely W, Burkard WP, Cesura AM, Kettler R, Lorez HP, Martin JR, Richards JG, Scherschlicht R, Da Prada M (1992) Biochemistry and pharmacology of moclobemide, a prototype RIMA. Psychopharmacol 106: S6-S14
Heinonen EH, Myllylä V, Sotaniemi K, Lammintausta R, Salonen JS, Antilla M, Saviljärvi M, Kotila M, Rinne UK (1989) Pharmacokinetics and metabolism of selegiline. Acta Neurol Scand 126: 93–99
Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17: 1285–1297
Kato T, Dong B, Ishii K, Kinemuchi H (1986) Brain dialysis: in vivo metabolism of dopamine and serotonin by monoamine oxidase A but not B in the striatum of unrestrained rats. J Neurochem 46: 1277–1282
Knoll J (1978) The possible mechanisms of action of (−)deprenyl in Parkinson's disease. J Neural Transm 43: 177–198
Knoll J (1983) Deprenyl (selegiline): the history of its development and pharmacological action. Acta Neurol Scand [Suppl] 95: 57–80
Konradi Ch, Svoma E, Jellinger K, Riederer P, Denney R, Thibault T (1988) Topographic immunocytochemical mapping of monoamine oxidase-A, monoamine oxidase-B and tyrosine hydroxylase in human post mortem brain stem. Neurosci 26: 791–780
Konradi C, Kornhuber J, Froelich L, Fritze J, Heinsen H, Beckmann H, Schulz E, Riederer P (1989) Demonstration of monoamine oxidase-A and-B in the human brainstem by a histochemical technique. Neurosci 33: 383–400
Melamed E, Youdim MBH (eds) (1990) Parkinson's disease: anatomy, physiology, and therapy. Raven Press, New York, pp 483–488 (Adv Neurol 53)
Paterson IA, Jurio AV, Berry MD, Zhu MY (1991) Inhibition of monoamine oxidase-B by (−)-deprenyl potentiates neuronal responses to dopamine agonists but does not inhibit dopamine catabolism in the rat striatum. J Pharmacol Exp Ther 258: 1019–1026
Provost J-C, Funck-Brentano C, Rovei V, D'Estanque J, Ego D, Jaillon P (1992) Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects. Clin Pharmacol Ther 52: 384–393
Reynolds GP, Elsworth JD, Blau K, Sandler M, Lees AJ, Stern GM (1978) Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 6: 542–544
Riederer P, Konradi C, Hebenstreet G, Youdim MBH (1989) Neurochemical perspectives to the function of monoamine oxidase. Acta Neurol Scand 126: 41–45
Roth M, Guelfi JD (1992) The efficacy of reversible monoamine oxidase inhibitors in depressive illness. Can J Psychiatry [Suppl 1]: 18–24
Saura J, Kettler R, Da Prada M, Richards JG (1992) Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6237 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain. J Neurosci 12: 1977–1999
Wachtel SR, Abercrombie ED (1994) L-3,4-dihydroxyphenylalanine-induced dopamine release in the striatum of intact and 6-hydroxydopamine-treated rats: differential effects of monoamine oxidase A and B inhibitors. J Neurochem 63: 108–117
Weiner M (1985) Norepinephrine, epinephrine, and the sympathomimetic amines. In: Goodman AG, Gillman LS, Rall TW, Murad (eds) Goodman and Gillman's the pharmacological basis of therapeutics, 7th edn. MacMillan, New York, pp 145–180
Westlund KN, Denney RM, Rose RM, Abell CW (1988) Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem. Neurosci 25: 439–456
Yahr MD, Duvoisin RC (1972) Drug therapy of parkinsonism. N Engl J Med 287: 20–24
Yahr MD, Mendoza MR, Moros D, Bergmann KJ (1983) Treatment of Parkinson's disease in early and late phases. Use of pharmacological agents with special reference to deprenyl (selegiline). Acta Neurol Scand [Suppl] 95: 95–102
Yahr MD, Elizan TS, Moros D (1989) Selegiline in the treatment of Parkinson's disease — long term experience. Acta Neurol Scand 126: 157–161
Youdim MBH (1990) Inhibitors of dopamine inactivating systems as antiparkinson drugs. In: Streifler MB, Korczyn AD, Melamed E, Youdim MBH (eds) Parkinson's disease: anatomy, pathology, and therapy. Raven Press, New York, pp 483–488 (Adv Neurol 53)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brannan, T., Prikhojan, A., Martínez-Tica, J. et al. In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striatal L-DOPA and dopamine metabolism. J Neural Transm Gen Sect 10, 79–89 (1995). https://doi.org/10.1007/BF02251224
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02251224