Effects of L - Dopa on Norepiilephrine Metabolism in the Brain

Rats received intracisternal 1aIlnorepinephrine and, after 5 min, intraperitoneal L-dopa (100 mg/kg); they were killed at intervals during the subsequent 24 hr. Their brains were assayed for norepinephrile, L-dopa, S-adenosylmethionine, and [aH]norepilnephrine and its metabolites. Rats that received L-dopa had markedly lower brain concentrations of S-adenosylnethionine and of O-methylated metabolites of [3Hlnorepinephlrine than controls. An increase (15-40%) in brain norepinephrine content and accelerated turnover of brain norepinephrine was also observed in the animals receiving L-dopa. These changes were all transient, lasting about 1 hr and coinciding with the period when appreciable amounts of l-dopa were detectable in the brain. The initial enzymatic reaction in the biosynthesis of brain catecholamines involves the formation of the catechol amino acid i-dihydroxyphenylalanine (L-dopa) from tyrosine. Once formed, the -dopa is immediately decarboxylated to form dopamine, which, in some neurons, is further transformned to norepinephrine (1, 2). Dopa cannot be detected normally in the brain or in the blood (3), and thus it is unlikely that circulating dopa is a physiological precursor for brain catecholamines. However, when exogenous dopa is administered to experimental animals, the concentration of dopamine in the brain increases (4, 5). This observation, coupled with the finding that dopamine concentrations measured at autopsy in brains of patients with Parkinson's disease are low (6), suggested that exogenous J-dopa might be useful in the treatment of Parkinsonism. That hypothesis has now been confirmed in numerous clinical studies (7-9). However, the importance of the conversion of dtopa to brain dopamine as the basis of its therapeutic action remains unclear. Recent studies in mice have shown that <0.1% of injected labeled L-dopa is detectable as brain catecholamines at any time after administration of the amino acid (10). L-Dopa is also known to influence the fates of other putative brain neurotransmitters in addition to dopamine. Its administration is followed by a reduction of brain serotonin concentration (11, 12), possibly because the dopamine formed in vivo competes with serotonin for intraneuronal storage sites (13); moreover, some (5, 14, 15) but not all (12) observers have reported increased concentrations of brain norepinephrine afterL z-dopa administration. If experimental animals are given doses of L-dopa similar to those used in the treatment of Parkinson's disease, a major portion of the administered catechol amino acid is rapidly metabolized by O-methylation to form 3-0-methyl-dopa and the 3-O-methylated and dea minated product of dopamnine, Abbreviation: SAMe, S-adenosylnethionine. homovanillic acid (10). A marked decrease in the brain concentration of the methyl donor S-adenosylmethionine (SAMe) is found during the hour after xdopa administration (6). This suggests that large amounts of SAMe are utilized in the formation of these rnethylated compounds. If that is so, idopa administration might interfere with a large number of methylation reactions in which SAMe serves as the methyl donor. One such reaction of major physiological significance is the inactivation of tissue catechols by 3-O-methylation (1), a process catalyzed by the enzyme catecholmethyl transferase (S-adenosylriethioiniie: catechol O-methyltransferase, EC 2.1.1.6) (17). The present studies were undertaken to examine the O-methylation of [alH]norepinephrine in the brains of rats receiving doses of dlopa equivalent to those used in the treatment of Parkinson's disease.