Regulation of intracellular dopamine levels by dopaminergic drugs: involvement of vesicular monoamine transporter.
Endogenous dopamine could serve as a susceptibility factor for dopaminergic neuronal death. Our previous study demonstrated that depletion of dopamine content induced by dopamine receptor agonist was relevant to neuroprotection. In the current study, we have investigated the mechanisms underlying the dopamine-lowering effect of dopaminergic drugs using pheochromocytoma (PC12) cells. The majority of agonistic or antagonistic ligands for the dopamine receptor reduced intracellular dopamine levels in PC12 cells. The reduction of dopamine content induced by (-)-pramipexole, a dopamine D(2)/D(3) receptor agonist, was not mediated by the activation of dopamine D(2)-like receptors. (-)-Pramipexole subtly suppressed the dopamine synthesis, but did not facilitate its metabolism. Dopamine was released just after stimulation with (-)-pramipexole, whereas the accumulative amount of released dopamine for 24 h was not increased. Furthermore, (-)-pramipexole prevented the uptake of [(3)H] dopamine into vesicles in a competitive manner. The dopaminergic drugs which gave rise to reduction in dopamine content also interfered with vesicular dopamine transport. These results suggest that dopaminergic drugs can reduce intracellular dopamine via inhibition of vesicular monoamine uptake.
Izumi
Yasuhiko
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Yamamoto
Noriyuki
N
Kume
Toshiaki
T
Katsuki
Hiroshi
H
Sawada
Hideyuki
H
Akaike
Akinori
A
D000704:Analysis of Variance; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001692:Biological Transport; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism*; D016716:PC12 Cells; D000077487:Pramipexole; D051381:Rats; D050493:Vesicular Monoamine Transport Proteins / Q000502:physiology*
D052160:Benzothiazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050493:Vesicular Monoamine Transport Proteins; D000077487:Pramipexole; D004298:Dopamine