Monoamine oxidase-A inhibitors and dopamine metabolism in rat caudatus: evidence that an increased cytosolic level of dopamine displaces reversible monoamine oxidase-A inhibitors in vivo.
The effects of reversible inhibitors of monoamine oxidase-A (moclobemide, Ro 41-1049, both 20 mg/kg, i.p., and brofaromine, 10 mg/kg, i.p.) on the outflow of dopamine (DA) and its metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) as well as of 5-hydroxyindoleacetic acid was investigated by trans-striatal microdialysis in rats. These drugs markedly increased the level of DA in the dialysis fluid by 100% of basal values and concomitantly reduced the output of 3,4-dihydroxy-phenylacetic acid and homovanillic acid by 90%. The presence of tetrodotoxin in the perfusion fluid decreased the basal DA outflow and virtually abolished the rise in DA efflux after moclobemide administration. On the other hand, tetrodotoxin did not counteract the DA outflow induced by Ro 4-1284 (1 mg/kg, i.p.), a tetrabenazine derivative which rapidly releases DA from vesicles and causes a massive increase in the concentration of extravesicular amine. The injection of Ro 4-1284 30 min after moclobemide, brofaromine or Ro 41-1049 induced a 6-fold increase in DA outflow, which was accompanied by a transient increase in 3,4-dihydroxyphenylacetic acid levels. This latter effect was more marked for moclobemide than for the other two reversible inhibitors tested and was not observed in rats given the irreversible inhibitor clorgyline (5 mg/kg, i.p.). These results support the view that a large increase in the concentration of endogenous substrates in the cytosol might displace reversible monoamine oxidase-A inhibitors from the enzyme active sites. Therefore, the microdialysis technique seems to be a reliable in vivo method for assessing the degree of reversibility of monoamine oxidase inhibitors.
Colzi
A
A
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
D'Agostini
F
F
Cesura
A M
AM
Borroni
E
E
Da Prada
M
M
D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D020912:Moclobemide; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D001549:Benzamides; D015306:Biogenic Monoamines; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; D012701:Serotonin; D013779:Tetrodotoxin; C038213:brofaromine; D020912:Moclobemide; D004298:Dopamine