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).