Apomorphine enantiomers' effects on dopamine metabolism: receptor and non-receptor related actions.
The enantiomers of apomorphine (APO) inhibited dopamine synthesis in rat striatal synaptosomes, with R(-)-APO being about twice as potent as S(+)-APO. Sulpiride, a DA receptor antagonist, partially antagonized the inhibitory effects of only (-)-APO, suggesting that (-)-APO's, but not (+)-APO's, effects on dopamine synthesis may be at least partially receptor-mediated. The addition of 6-methyl-5,6,7,8-tetrahydrobiopterine (6-MPH4), an artificial cofactor for tyrosine hydroxylase, partially antagonized the inhibitory effects of both enantiomers, being considerably more effective against the (+)enantiomer. These data suggest that the APO enantiomers may directly inhibit enzymes within the synaptosome which regulate dopamine synthesis. Furthermore, investigations measuring DA synthesis rates in synaptosomes that had been pre-incubated with (-)-APO and then washed to remove the (-)-APO in the medium, indicate that (-)-APO may be retained by synaptosomes. Preliminary studies measuring the accumulation of [3H](-)-APO by synaptosomes also suggest that synaptosomes can accumulate APO. Although both APO enantiomers suppressed DA synthesis in vitro, only (-)-APO reduced striatal DA metabolite concentrations in vivo, and this reduction was prevented by haloperidol, a DA receptor antagonist. In addition, 6-MPH4 prevented the decrease in the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) produced by (-)-APO but not the decrease in the DA metabolite homovanillic acid (HVA).
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001708:Biopterins; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis*; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D011622:Pterins / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D013237:Stereoisomerism; D013469:Sulpiride / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism
D011622:Pterins; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D001708:Biopterins; D013469:Sulpiride; C017523:6-methyltetrahydropterin; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine; D006719:Homovanillic Acid