Effects of apomorphine enantiomers and of lisuride on 3,4-dihydroxyphenylalanine production in striatal synaptosomes.
The effects of lisuride and of the R(-)- and S(+)-enantiomers of apomorphine were examined on 3,4-dihydroxyphenylalanine (DOPA) production by striatal synaptosomes and by crude, soluble striatal tyrosine hydroxylase. Due to their catechol structure, the enantiomers were almost equally effective in blocking soluble tyrosine hydroxylase (EC 1.14.16.2) (IC50 = 470 and 890 nM for R(-)- and S(+)-apomorphine, respectively), provided incubations were performed at pH 7.2 with 1 mM tetrahydrobiopterin as cofactor. The enantiomers were similarly effective in blocking synaptosomal DOPA production (IC50 = 410 and 970 nM for R(-)- and S(+)-apomorphine, respectively). As S(+)-apomorphine but not R(-)-apomorphine is considered to be a dopamine antagonist, these results support the assumption that the block of synaptosomal DOPA production by both apomorphine enantiomers is due to a direct inhibition of tyrosine hydroxylase. Lisuride at high concentrations (10-100 microM) blocked DOPA production in striatal synaptosomes; simultaneously, intrasynaptosomal dopamine was depleted. These data support the assumption that lisuride inhibits DOPA production indirectly, similar to reserpine. In accordance with this assumption, lisuride was without effect on DOPA production in dopamine-depleted synaptosomes. These results demonstrate that inhibition of synaptosomal DOPA production by at least some dopamine agonists may be explained by direct inhibitory effects on tyrosine hydroxylase.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000096:biosynthesis; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D002396:Catechols / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis*; D004298:Dopamine / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008090:Lisuride / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
D002396:Catechols; D004873:Ergolines; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; D004295:Dihydroxyphenylalanine; D008090:Lisuride; D006220:Haloperidol; C034221:catechol; D001058:Apomorphine; D004298:Dopamine