Effect of acute levodopa on brain catecholamines after selective MAO and COMT inhibition in male rats.
Interactions between a selective catechol-O-methyltransferase (COMT) inhibitor OR-462 and a monoamine oxidase (MAO)-A inhibitor clorgyline were studied measuring concentrations of L-dopa, dopamine and their metabolites in the rat hypothalamus and striatum after administration of levodopa/carbidopa (15/30 mg/kg i.p.). Part of the experiments were performed in rats pretreated with 6-OH-dopamine (6-OHDA) intracerebroventricularly (i.c.v.) to determine whether changes in dopamine metabolism occurred inside or outside catecholaminergic neurons. OR-462 was an effective COMT inhibitor at the doses 3 and 30 mg/kg i.p. Inhibition of 3-O-methyldopa (3-OMD) formation from L-dopa was reflected in the hypothalamus (45-81% decrease) and striatum (87-88% decrease), since 3-OMD penetrates the blood-brain barrier. Homovanillic acid (HVA) was decreased only in the striatum at 30 mg/kg of OR-462. Clorgyline (8 and 32 mg/kg i.p.) decreased 3,4-dihydroxyphenylacetic acid (DOPAC) formation in the hypothalamus and striatum by 61-91%. When given together, OR-462 and clorgyline elevated hypothalamic dopamine levels 3.2-4.6-fold, but striatal dopamine only 1.3-1.9-fold. The formation of 3-OMD and DOPAC remained suppressed and even brain HVA levels were decreased by 51-97%. 6-OHDA treatment decreased striatal and hypothalamic dopamine by 50% and noradrenaline by 75%. In these animals levodopa/carbidopa increased brain L-dopa 2.4-4-fold, those of 3-OMD 1.2-1.7-fold compared to intact animals, but the synthesis and metabolism of dopamine and the effects of COMT and MAO inhibitors were not significantly changed. Levodopa/carbidopa treatment decreased significantly prolactin and thyrotropin levels in serum but none of the additional treatments changed this action.
Männistö
P T
PT
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Tuomainen
P
P
Toivonen
M
M
Törnwall
M
M
Kaakkola
S
S
D000818:Animals; D002230:Carbidopa / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006892:Hydroxydopamines; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D009498:Neurotoxins; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains
D002395:Catecholamines; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006892:Hydroxydopamines; D009498:Neurotoxins; D007980:Levodopa; D016627:Oxidopamine; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D002230:Carbidopa; D004298:Dopamine