Acute L-DOPA pretreatment potentiates 6-hydroxydopamine-induced toxic effects on nigro-striatal dopamine neurons in mice.
We have studied the effect of various agents on the decreases in striatal levels of dopamine (DA) and its metabolites which were observed 14 days after an intracerebroventricular (i.c.v.) administration of 50 micrograms 6-hydroxydopamine (6-OHDA) to mice. A pretreatment of mice with either a tyrosine hydroxylase inhibitor (alpha-methyl-p-tyrosine), a D2 receptor agonist (bromocriptine) or antagonist (haloperidol), or a vesicular uptake inhibitor (tetrabenazine) did not modify the 6-OHDA-induced decreases in DA and metabolites, indicating that DA synthesis, vesicular storage and neuronal firing rates are not mainly involved in the 6-OHDA-induced toxicity on the DA neurons. Conversely, a pretreatment with L-DOPA + benserazide potentiated the 6-OHDA-induced decreases in striatal levels of DA, homovanillic acid and 3-methoxy-tyramine. This effect was not due to an increased 6-OHDA uptake via the neuronal carrier since a pretreatment with L-DOPA + benserazide, performed 1-1.5 h before sacrifice, decreased the apparent affinity of the uptake, an effect which disappeared when considering the total DA concentration present in incubation medium ([3H]DA and cold released DA). In conclusion, potentiation of the 6-OHDA neurotoxicity by L-DOPA rises again the important problem of the safety of the latter drug in therapeutics.
Naudin
B
B
Laboratoire de Neuropsychopharmacologie Expérimentale, Faculté de Médecine et Pharmacie, Saint Etienne du Rouvray, France.
Bonnet
J J
JJ
Costentin
J
J
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004357:Drug Synergism; D004563:Electrochemistry; D066298:In Vitro Techniques; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity*; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013565:Sympatholytics / Q000633:toxicity*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002352:Carrier Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D013565:Sympatholytics; D007980:Levodopa; D016627:Oxidopamine; D004298:Dopamine