Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo.
Acute inhibition of monoamine oxidase B (MAO-B) in the rat does not affect striatal dopamine (DA) metabolism, but chronic MAO-B inhibition with deprenyl has been reported to increase the release of striatal DA, as shown using in vitro techniques. To see whether chronic MAO-B inhibition also causes an increase in DA release in vivo, rats were treated for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [R(+)-N-propargyl-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). Concentric 4-mm-long microdialysis probes were implanted in the left striatum under pentobarbital/chloral hydrate anesthesia on day 21, and microdialysate DA, 3,4, dihydroxyacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenyl 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) pmol/20 min. Levels of DOPAC and HVA were reduced only in the clorgyline-treated group. The incremental release of DA induced by depolarizing concentration of K+ (100 mM bolus of KCl in perfusate) was significantly greater in clorgyline- and deprenyl-treated rats and elevated (nonsignificantly) in TVP-1012-treated rats. Chronic treatment with the MAO-B inhibitors reduced striatal MAO-B activity by 90%, with 15% (TVP-1012) or 40% (deprenyl) inhibition of MAO-A. Clorgyline inhibited MAO-A by 95%, with 30% inhibition of MAO-B. A single dose of deprenyl (0.25 mg/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 release by chronic MAO-B inhibition does not appear to be dependent on production of amphetamine-like metabolites of the inhibitor. Possible mechanisms for the release-enhancing effect of the MAO-B inhibitors include elevation in levels of endogenous beta-phenylethylamine, or an inhibition of DA reuptake, which develops only on chronic administration, because both deprenyl and TVP-1012 have only very weak effects on amine uptake in acute experiments.
Lamensdorf
I
I
Pharmacology Unit, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Youdim
M B
MB
Finberg
J P
JP
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003010:Clorgyline / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004334:Drug Administration Schedule; D006719:Homovanillic Acid / Q000378:metabolism; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D007189:Indans; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; C031967:rasagiline; D015102:3,4-Dihydroxyphenylacetic Acid; D012642:Selegiline; D008995:Monoamine Oxidase; D003010:Clorgyline; D006719:Homovanillic Acid