IN-VITRO EFFECTS ON MONOAMINE UPTAKE AND RELEASE BY THE REVERSIBLE MONOAMINE OXIDASE-B INHIBITORS LAZABEMIDE AND N-(2-AMINOETHYL)-P-CHLOROBENZAMIDE - A COMPARISON WITH L-DEPRENYL

To investigate whether the reversible monoamine oxidase-B (MAO-B) inhibitors lazabemide and Ro 16-6491 have any additional effect on monoamine uptake and release, in vitro experiments were performed on rat forebrain synaptosomes and blood platelets. The effects of the two drugs were compared with those of L-deprenyl, the well-known irreversible MAO-B inhibitor which is reported to affect amine uptake. Both lazabemide and Ro 16-6491 behaved as weak inhibitors of [H-3]monoamine uptake by synaptosomes, with a similar rank order of potency for amine uptake inhibition (noradrenaline (NA) greater than or equal to 5-hydroxytryptamine (5 HT) > dopamine (DA)). The IC50 values for lazabemide and Ro 16-6491, respectively, were: 86 mu M and 90 mu M for NA uptake; 123 mu M and 90 mu M for 5HT uptake; > 500 mu M and > 1000 mu M for DA uptake. L-Deprenyl (rank order of inhibitory potency: NA > DA > 5HT) was four to 10 times more potent than either compound in inhibiting [H-3]catecholamine uptake (IC50 = NA 23 mu M, DA 109 mu M), and two to three times less potent in inhibiting 5 HT uptake (IC50, 233 mu M). Lazabemide and Ro 16-6491 also differed from L-deprenyl in their ability to induce release of endogenous monoamines from synaptosomes. Thus, Ro 16-6491 (500 mu M) induced a greater 5 HT release than did L-deprenyl, but was less effective than L-deprenyl in releasing DA. On the contrary, lazabemide was almost completely inactive on either 5 HT and DA release. The differential effect of the three MAO-B inhibitors on synaptosome 5 HT uptake and release was confirmed by [C-14]5HT uptake and liberation experiments with isolated rat platelets. The data indicate that the reversible MAO-B inhibitors lazabemide and Ro 16-6491 at relatively high concentrations possess amine uptake-inhibiting properties. With regard to the effects examined, lazabemide markedly differs from L-deprenyl since it does not interfere with DA uptake nor induce amine release from synaptosomes.