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

Abstract

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.S 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.

In vivo, noradrenaline is a substrate for rat brain monoamine oxidase A and B

“…In agreement with in vivo results of Yang & Neff (1974) and Green et al (1977) who used the whole brain, in the present study it was found that clorgyline rather than deprenyl caused a rise in NA concentrations of hypothalamus, caudate nucleus and the rest of the brain without the latter regions. This rise is even larger when L-DOPA is given to rats in combination with clorgyline, but there is very little change either after (-)-deprenyl alone or (-)-deprenyl plus L-DOPA treatment.…”

“…After administration of tranylcypromnine, the non-selective MAO inhibitor, the brain NA level also rises to the concentrations seen after the combination of clorgyline and (-)-deprenyl, with a further increase after L-DOPA. These results are very similar to those obtained for the in vivo deamination of 5-HT and dopamine in the rat brain (Green & Youdim, 1975;Green et al, 1977 The present study thus indicates that while in vitro noradrenaline may be deaminated exclusively by MAO A Suzuki et al, 1979;Kinemuchi et al, 1979), when this enzyme form is fully inhibited in vivo, MAO B can continue to act on noradrenaline, albeit at a slower rate, indicating that the affinity of MAO B as compared to MAO A for NA is much lower. These results are not in agreement with the studies of Neff, Yang & Goridis (1973) and others (Goridis & Neff, 1971;Neff & Fuentes, 1976) who reported that noradrenaline was a specific substrate for MAO A alone in the rat brain.…”

Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study

“…Thus, only a mixed inhibition of type A and type B MAO obtained with pargyline and high concentrations of clorgyline and deprenyl, is able to affect clearly the functioning of the dopaminergic neurones of the rat mesencephalon. It has already been proposed that a complete inhibition of both forms of MAO is required to elevate maximally extracellular dopamine (Butcher et al, 1990;Juorio et al, 1994) and to induce dopamine-related behavioural activation (Green et al, 1977). In order to explain the lack of effects of low concentrations of clorgyline on firing discharge, it is conceivable that the preferential blockade of MAO A by this drug might switch the metabolism of dopamine to extraneuronal non-dopaminergic sites where MAO B still plays an important role (Schoepp & Azzaro, 1982;1983;Butcher et al, 1990).…”

“…Furthermore, there is evidence that a rather selective inhibition of MAO A can be obtained by a low concentration (nM) of clorgyline while a quite selective MAO B inhibition is caused by (-)-deprenyl treatment (nanomolar range) (Johnston, 1968;Knoll & Magyar, 1972;Harsing & Vizi, 1984). Although it has been demonstrated that the inhibition of MAO with pargyline prevents the formation of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and increases the efflux of dopamine and 3-methoxytyramine (3-MT) from the striatum of animals pretreated with this drug (Harsing & Vizi, 1984;Imperato & DiChiara, 1984;Kato et al, 1986;Wood et al, 1987;Butcher et al, 1990;Juorio et al, 1994), there are still controversial results about the relative effects of MAO A and B inhibition on dopamine metabolism (Houslay et al, 1976;Green et al, 1977;Schoepp & Azzaro, 1983;Harsing & Vizi, 1984;Juorio et al, 1994 (Engberg et al, 1991).…”

“…Monoamine oxidases (MAO) are mitochondrial enzymes which participate in the degradation of dopamine (Yang & Neff, 1974;Green et al, 1977;Weiner & Molinoff, 1989;Juorio et al, 1994). Two forms of MAO (A and B) (Johnston, 1968;Yang & Neff, 1974;Schoepp & Azzaro, 1982) have been described so far with a different distribution in the brain: (a) the MAO A are mainly located intraneuronally in the dopaminergic cells (Roffler-Tarlov et al, 1971;Marsden et al, 1972;Demarest et al, 1980;Commissioning, 1985).…”