Effects of L-dopa on epinephrine concentration in rat brain: possible role of inhibition of norepinephrine N-methyltransferase by S-adenosylhomocysteine.
L-Dopa injected at 200 mg/kg i.p. into rats caused a slight reduction in hypothalamic concentration of epinephrine and completely prevented the accumulation of epinephrine after monoamine oxidase inhibition. The lowering of epinephrine concentration was greater with L-dopa than with D-dopa, was dose-related over a dosage range of 50 to 200 mg/kg of L-dopa and was not prevented by a dopamine receptor antagonist. Hypothalamic norepinephrine N-methyltransferase activity measured in vitro was not altered in rats treated with L-dopa. L-Dopa injection decreased S-adenosylmethionine (SAMe) concentration and increased S-adenosylhomocysteine (SAH) concentration in hypothalamus, probably a result of extensive O-methylation of L-dopa and its metabolites. The decrease in SAMe and epinephrine concentration and the increase in SAH concentration occurred at lower doses of L-dopa in carbidopa-pretreated rats than in control rats. Norepinephrine N-Methyl-transferase activity assayed in vitro was markedly inhibited by SAH; the inhibition was competitive with SAMe as the variable substrate and the Ki for SAH was 1.9 x 10(-5) M. Increasing the SAH/SAMe ratio in in vitro experiments sharply reduced norepinephrine N-methyltransferase activity. The apparent inhibition of hypothalamic epinephrine synthesis in vivo after L-dopa injection is suggested to be a consequence of the increased SAH/SAMe ratio.
D000818:Animals; D004837:Epinephrine / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D012435:S-Adenosylhomocysteine / Q000378:metabolism / Q000502:physiology; D012436:S-Adenosylmethionine / Q000378:metabolism
D008996:Monoamine Oxidase Inhibitors; D007980:Levodopa; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine