EFFECT OF LONG-TERM TREATMENT WITH SELECTIVE MONOAMINE-OXIDASE-A AND MONOAMINE-OXIDASE-B INHIBITORS ON DOPAMINE RELEASE FROM RAT STRIATUM IN-VIVO

Acute inhibition of monoamine oxidase B (MAO-B) in the rat does not af fect striatal dopamine (DA) metabolism, but chronic MAO-B inhibition w ith deprenyl has been reported to increase the release of striatal DA, as shown using in vitro techniques. To see whether chronic MAO-B inhi bition also causes an increase in DA release in vivo, rats were treate d for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [R(+)-N-prop argyl-1-aminoindan mesylate; 0.05 mg/kg], an irreversible inhibitor of MAO-B that is not metabolized to amphetamines, clorgyline (0.2 mg/kg) , or saline (all doses once daily by subcutaneous injection). Concentr ic 4-mm-long microdialysis probes were implanted in the left striatum under pentobarbital/chloral hydrate anesthesia on day 21, and microdia lysate DA, 3,4,dihydroxyacetic acid (DOPAC), and 4-hydroxy-3-methoxyph enyl acetic acid (HVA) were determined in the conscious animals on day 22. Baseline levels of DA were as follows: control, 0.34 +/- 0.04 (n = 13); deprenyl, 0.88 +/- 0.10 (n = 8, p < 0.01); TVP-1012, 0.94 +/- 0 .20 (n = 7, p < 0.01); clorgyline, 0.90 +/- 0.12 (n = 7, p < 0.01) pmo l/20 min. Levels of DOPAC and HVA were reduced only in the clorgyline- treated group. The incremental release of DA induced by depolarizing c oncentration of K+ (100 mM bolus of KCl in perfusate) was significantl y greater in clorgyline- and deprenyl-treated rats and elevated (nonsi gnificantly) in TVP-1012-treated rats. Chronic treatment with the MAO- B inhibitors reduced striatal MAO-B activity by 90%, with 15% (TVP-101 2) or 40% (deprenyl) inhibition of MAO-A. Clorgyline inhibited MAO-A b y 95%, with 30% inhibition of MAO-B. A single dose of deprenyl (0.25 m g/kg, 24 h before microdialysis) had no significant effect on striatal efflux of DA. The results show that DA metabolism was reduced only by clorgyline, whereas neuronal release of DA was enhanced by both MAO-A and MAO-B inhibitors on chronic administration. The enhanced DA relea se by chronic MAO-B inhibition does not appear to be dependent on prod uction of amphetamine-like metabolites of the inhibitor. Possible mech anisms for the release-enhancing effect of the MAO-B inhibitors includ e elevation in levels of endogenous beta-phenylethylamine, or an inhib ition of DA reuptake, which develops only on chronic administration, b ecause both deprenyl and TVP-1012 have only very weak effects on amine uptake in acute experiments.