Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 324, Issue 2, pp 79–87 | Cite as

Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain

  • Anna-Lena Ask
  • Ingrid Fagervall
  • Svante B. Ross
Article

Summary

The prevention by six reversible and selective monoamine oxidase-A (MAO-A) inhibitors (α-ethyltryptamine, harmaline, 4-methoxyamphetamine, amiflamine [FLA 336(+)], N-desmethylamiflamine [FLA 788(+)] and N,N-desmethylamiflamine [FLA 668(+)] of the phenelzineinduced irreversible MAO inhibition in the rat brain was examined. By using crude synaptosome preparations of hypothalamus and striatum incubated with low substrate concentrations of 14C-serotonin (1×10−7 M), 14C-noradrenaline (2.5×10−7 M) and 14C-dopamine (2.5×10−7 M) in the absence and presence of selective amine uptake inhibitors (alaproclate, maprotiline and amfonelic acid, respectively), it was possible to determine the deaminating activities inside and outside the specific aminergic synaptosomes. Thus, with this technique the protection of MAO by the reversible inhibitors administered orally 1 h prior to the subcutaneous injection of phenelzine against the phenelzine effect could be determined inside and outside the specific aminergic neurons. It was found that α-ethyltryptamine, 4-methoxyamphetamine and particularly amiflamine and FLA 788(+) were more potent inside than outside the serotonergic neurons. FLA668(+) was a selective inhibitor of noradrenergic MAO, to which also 4-methoxyamphetamine, amiflamine and FLA 788(+), but not α-ethyltryptamine had some preference. Harmaline had no certain preference for MAO in any of the aminergic neurons. At high doses of FLA 668(+) a preference for dopaminergic MAO was observed. Since pretreatment of the rats with norzimeldine or desipramine antagonized the preferences for serotonergic or noradrenergic MAO, it is plausible to conclude that the compounds showing these preferences are accumulated in the neurons by the membranal uptake systems.

Key words

Monoamine oxidase type A inhibitors Serotonin Amiflamine α-Ethyltryptamine 4-Methoxyamphetamine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ask A-L, Fagervall I, Ross SB (1982a) Evidence for a selective inhibition by FLA 336(+) of the monoamine oxidase in serotonergic neurons in the rat brain. Acta Pharmacol Toxicol 51:395–396Google Scholar
  2. Ask A-L, Högberg K, Schmidt L, Kiessling H, Ross SB (1982b) (+)-4-Dimethylamino-2,α-dimethylphenethylamine [FLA 336(+)], a selective inhibitor of the A form of monoamine oxidase in the rat brain. Biochem Pharmacol 31:1401–1406Google Scholar
  3. Florvall L, Persson M-L (1982) N-Desmethyl analogues of (+)-4-dimethylamino-2, α-dimethylphenethylamine. Synthesis and configurational relationships. Acta Chem Scand B36:141–146Google Scholar
  4. Florvall L, Ask A-L, Ögren S-O, Ross SB (1978) Selective monoamine oxidase inhibitors. 1. Compounds related to 4-aminophenethylamine. J Med Chem 21:56–63Google Scholar
  5. Furchgott RF, Sanchez Garcia P, Wakade AR, Cervoni P (1971) Interactions of bretylium and other drugs on guinea-pig atria: evidence for inhibition of neuronal monoamine oxidase by bretylium. J Pharmacol Exp Ther 179:171–185Google Scholar
  6. Green AL, El Hait MAS (1980a) A new approach to the assessment of the potency of reversible monoamine oxidase inhibitors in vivo, and its application to (+)-amphetamine, p-methoxyamphetamine and harmaline. Biochem Pharmacol 29:2781–2789Google Scholar
  7. Green AL, El Hait MAS (1980b) p-Methoxyamphetamine, a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo. J Pharm Pharmacol 32:262–266Google Scholar
  8. Horita A, McGrath WR (1960) The interaction between reversible and irreversible monoamine oxidase inhibitors. Biochem Pharmacol 3:206–211Google Scholar
  9. Maycock A-L, Abeles RH, Salach JI, Singer TP (1976) The structure of the covalent adduct formed by the interaction of 3-dimethylamino-1-propyne and the flavine of mitochondrial amine oxidase. Biochemistry 15:114–125Google Scholar
  10. Ögren S-O, Ask A-L, Holm A-C, Florvall L, Lindbom L-O, Lundström J, Ross SB (1981) Biochemical and pharmacological properties of a new selective and reversible monoamine oxidase inhibitor, FLA 336(+). In: Youdim MBH, Paykel ES (eds) Monoamine oxidase inhibitors — the state of the art. John Wiley & Sons London, pp 103–112Google Scholar
  11. Pletscher A, Besendorf J (1959) Antagonism between harmaline and long-acting monoamine oxidase inhibitors concerning the effect on 5-hydroxytryptamine and norepinephrine metabolism in the brain. Experientia 15:25–26Google Scholar
  12. Ross SB (1979) Interactions between reserpine and various compounds on the accumulation of [14C] 5-hydroxytryptamine and [3H] noradrenaline in homogenates from rat hypothalamus. Biochem Pharmacol 28:1085–1088Google Scholar
  13. Ross SB, Ask A-L (1980) Structural requirements for uptake into serotoninergic neurons. Acta Pharmacol Toxicol 46:270–277Google Scholar
  14. Ross SB, Kelder D (1979) Inhibition of 3H-dopamine accumulation in reserpinized and normal rat striatum. Acta Pharmacol Toxicol 44:329–335Google Scholar
  15. Singer TP (1979) Active site-directed irreversible inhibitors of monoamine oxidase. In: Singer TP, von Koff RW, Murphy DL (eds) Monoamine oxidase: structure function and altered function. Academic Press, New York, pp 7–24Google Scholar
  16. Steppeler A, Starke K (1980) Selective inhibition by amezinium of intraneuronal monoamine oxidase. Naunyn-Schmiedeberg's Arch Pharmacol 314:13–16Google Scholar
  17. Urwyler S, von Wartburg J-P (1981) Uptake and metabolism of catecholamines in rat brain synaptosomes: studies on the contribution of monoamine oxidase. Biochem Pharmacol 30:2777–2785Google Scholar
  18. Zirkle CL, Kaiser C (1964) Monoamine oxidase inhibitors (nonhydrazine). In: Gordon M (ed) Psychopharmacological agents vol 1. Academic Press, New York, pp 445–554Google Scholar

Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • Anna-Lena Ask
    • 1
  • Ingrid Fagervall
    • 1
  • Svante B. Ross
    • 1
  1. 1.Research and Development LaboratoriesAstra Läkemedel ABSödertäljeSweden

Personalised recommendations