Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propa
Striatal extracellular fluid concentrations of dopamine and metabolites in response to direct striatal administration of two L-DOPA boluses administered sequentially were determined in three rhesus monkeys during halothane anesthesia. Whereas in an initia
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Summary. Striatal extracellular fluid concentrations of dopamine and metabolites in response to direct striatal administration of two L-DOPA boluses administered sequentially were determined in three rhesus monkeys during halothane anesthesia. Whereas in an initial microdialysis run, generation of dopamine was less following the second L-DOPA bolus than the first, in a subsequent run, in which the selective MAO-B inhibitor R( + )-Npropargyl-1-aminoindan (rasagiline) was administered systemically (O.2mg/ kg s.c.) between the two L-DOPA boluses, generation of dopamine was greater following the second bolus. Introduetion Dopamine (DA) is a substrate für both types of monoamine oxidase (MAO) A and B, but its in vivo metabolism by MAO depends on the subtype of the enzyme present within the neuron and at the site of uptake following neuronal release. Following synthesis of DA from exogenous L-DOPA in the brain, metabolism will depend on the type of enzyme present at sites of decarboxylation of the L-DOPA, and at the site of uptake of the DA formed. Selective inhibition of MAO type B by ( - )-deprenyl is effective in potentiating the anti-Parkinsonian efficacy of L-DOPA in human patients who are experiencing loss of response to L-DOPA (Birkmayer et al., 1975). Brain tissue from such deprenyl-treated patients shows increased levels of dopamine (DA) and reduced levels of deaminated DA metabolites (Riederer and Youdim, 1986), indicating that in the human, DA formed from exogenous LDOPA is metabolised by MAO-B. Used in monotherapy in parkinsonian subjects, (- )-deprenyl possesses a symptomatic effect (Parkinson's Study Group, 1993), indicating that endogenously released DA is also metabolised by MAO-B, although deprenyl mayaiso have DA releasing properties which could be responsible für this effect (KnolI, 1978). J. P. M. Finberg et al. (eds.), MAO — The Mother of all Amine Oxidases © Springer-Verlag Wien 1998
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J. P. M. Finberg et al.
In human brain, about 75% of the MAO activity towards a joint substrate such as tyramine is type B, but the dopaminergic cells of the nigro-striatal pathway contain only MAO-A, as shown by immunohistochemical and ligand binding techniques (Westlund et al., 1985; Richards et al., this volume). In the rat, in which brain MAO activity is about 55% MAO-A (Tipton et al., 1976), striatal extracellular fluid DA levels are increased by inhibition of MAO-A but not MAO-B (Colzi et al., 1990). No comparable data for the effect of selective MAO inhibition on striatal DA levels exist in primate species. We therefore carried out an in vivo microdialysis study in the rhesus monkey to study the effect of selective inhibition of MAO-B on DA produced from LDOPA. The L-DOPA was administered directly into the striatum, in order to study striatal generation of DA without modification of its release by activation of somatodendritic receptors, as may follow systemic L-DOPA (Finberg et al., 1995). We used the selective MAO-B inhibitor R( + )-N-propargyl-1aminoindan (rasagiline; Finberg et al., 1995), which is no
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