Effect of high single doses of levodopa and carbidopa on brain dopamine and its metabolites: modulation by selective inhibitors of monoamine oxidase and/or catechol-O-methyltransferase in the male rat.
The upper limits of striatal and hypothalamic dopamine formation and metabolism in the rat were defined after acute levodopa/carbidopa (100/100 mg/kg) in combination with MAO (clorgyline; 32 mg/kg or pargyline; 100 mg/kg) and/or COMT inhibitors (OR-462, OR-611, Ro 41-0960, 30 mg/kg). Striatal and hypothalamic dopa and 3-OMD levels increased several hundred times after levodopa/carbidopa treatment alone. Dopamine, DOPAC, HVA and 3-MT levels elevated also but noradrenaline and 5-HT did not. Clorgyline further increased 3-OMD, dopamine and 3-MT concentrations while DOPAC and HVA levels decreased. These changes were even more pronounced after pargyline. In the striatum, all COMT inhibitors (with levodopa/carbidopa) blocked 3-OMD formation but elevated neither dopamine nor DOPAC levels. OR-462 increased dopa levels. Only Ro 41-0960, the brain penetrating compound, blunted HVA levels. All three COMT inhibitors decreased high 3-OMD levels evoked by MAO inhibitors (+ levodopa/carbidopa). In pargyline-treated rats, COMT inhibitors did not alter dopamine, DOPAC or HVA levels but all of them decreased significantly 3-MT levels, particularly Ro 41-0960. Striatal dopamine levels increased maximally 6 times compared to those in the saline-treated controls. In the hypothalamus, COMT inhibitors decreased 3-OMD levels to 1/5-1/30 of those after levodopa/carbidopa alone. COMT inhibitors suppressed 3-OMD formation also in clorgyline and pargyline (+ levodopa/carbidopa) treated rats. After clorgyline, OR-611 and Ro 41-0960 increased high dopamine levels but only Ro 41-0960 suppressed HVA and 3-MT levels. None of the COMT inhibitors changed the high dopamine and low DOPAC levels after pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)
Männistö
P T
PT
University of Helsinki, Department of Pharmacology and Toxicology, Finland.
Tuomainen
P
P
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002230:Carbidopa / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000502:physiology; D010908:Pituitary Hormones, Anterior / Q000096:biosynthesis; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains
D065098:Catechol O-Methyltransferase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D010908:Pituitary Hormones, Anterior; D007980:Levodopa; D002230:Carbidopa; D004298:Dopamine; D009638:Norepinephrine