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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
Author(s) -
GREEN A.R.,
MITCHELL B.D.,
TORDOFF ANN F.C.,
YOUDIM M.B.H.
Publication year - 1977
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1977.tb07506.x
Subject(s) - tranylcypromine , clorgyline , dopamine , monoamine oxidase , chemistry , endocrinology , medicine , monoamine oxidase b , serotonin , monoamine neurotransmitter , norepinephrine , pharmacology , enzyme , biology , biochemistry , receptor
1 Tranylcypromine (20 mg/kg) administration to rats totally inhibited brain monoamine oxidase (MAO) oxidation of 5‐hydroxytryptamine (5‐HT), phenylethylamine and dopamine as measured in vitro. When l ‐3,4‐dihydroxyphenylalanine ( l ‐DOPA) (50 mg/kg) was given 30 min after the tranylcypromine, brain dopamine and noradrenaline concentrations rose markedly and the rats displayed characteristic behavioural changes and locomotor activity. 2 Clorgyline (5 mg/kg) administration inhibited 5‐HT oxidation by almost 100% but phenylethylamine by only 29% while (‐)‐deprenil (5 mg/kg) injection almost totally inhibited phenylethylamine oxidation and inhibited 5‐HT metabolism by only 31%. Administration of l ‐DOPA after pretreatment with either drug did not alter brain dopamine or noradrenaline concentrations and the animals did not display any behavioural changes. 3 Administration of clorgyline plus (‐)‐deprenil (5 mg/kg of each) almost totally inhibited oxidation of both phenylethylamine and 5‐HT; there was a large rise of brain dopamine and noradrenaline concentrations and the animals displayed the behavioural changes observed when tranylcypromine and l ‐DOPA had been given. 4 The effects of tranylcypromine (20 mg/kg) on brain 5‐HT, dopamine and noradrenaline concentrations up to 48 h after injection were recorded. Brain 5‐HT concentrations were considerably elevated for 18 h after injection and then fell steadily. In contrast, brain dopamine concentrations rose slightly and remained at this level for 48 h while noradrenaline levels doubled and also remained at this level for 48 hours. 5 When l ‐tryptophan (50 mg/kg) was given at various times after tranylcypromine the characteristic hyperactivity syndrome appeared at 12 h but not 18 h after tranylcypromine and a further rise in brain 5‐HT was only observed at 12 hours. When l ‐DOPA (50 mg/kg) was given at various times after tranylcypromine a further large rise in brain dopamine and noradrenaline occurred at 12 h but not at 18 h and all the behavioural changes were observed only at 12 hours. 6 Measurement of MAO activity at the above times after tranylcypromine showed that the half‐life of recovery of the enzyme activity with 5‐HT and dopamine as substrates was 4.5 days and 8.5 days with phenylethylamine as substrate. Inhibition of MAO oxidation of dopamine and 5‐HT was approximately 85%, 18 h after tranylcypromine injection. 7 It is concluded from both the studies with clorgyline and deprenil and the recovery of MAO activity after tranylcypromine, that dopamine is metabolized by both Type A and Type B MAO in vivo and that it is only when both forms are almost totally inhibited that there is an increase in dopamine and 5‐HT functional activity, as judged by the appearance of the hyperactivity syndromes.