(+)MK-801 prevents the DDC-induced enhancement of MPTP toxicity in mice.
In order to reach deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, MK-801, a non-competitive antagonist of NMDA receptors, has been used as a tool to study the role of excitatory amino acids. In agreement with previous reports, (+)MK-801 did not significantly affect either striatal dopamine (DA) or tyrosine-hydroxylase (TH) activity in MPTP-treated animals. On the contrary (+)MK-801, but not (-)MK-801 significantly reduced the DDC + MPTP-induced fall in striatal DA and TH activity. A similar preventing effect on DA metabolites (DOPAC and HVA) and HVA/DA ratio was observed. The number of TH+ neurons in the substantia nigra (SN) of (+)MK-801-pretreated mice was not significantly different from that of control animals, indicating that this treatment specifically antagonized the extensive DDC-induced lesion of dopaminergic cell bodies in this brain area. (+)MK-801 treatment did not affect the DDC-induced changes of striatal MPP+ levels, suggesting that the observed antagonism of MK-801 against DDC is not due to MPP+ kinetic modifications. Pretreatment with the MAO-B inhibitor, L-deprenyl, or with the DA uptake blocker, GBR 12909, completely prevented the marked DA depletion elicited by DDC + MPTP within the striatum. Both treatments also protected from the fall in DA metabolites and TH activity as well. This indicates that DDC-induced potentiation is dependent upon MPP+ production and its uptake by the dopaminergic nerve terminals. All these findings suggest that NMDA receptors play a crucial role in the DDC-induced enhancement of MPTP toxicity.
Vaglini
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Institute of Pharmacology, School of Medicine, University of Pisa, Italy.
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D015655:1-Methyl-4-phenylpyridinium / Q000032:analysis; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D004050:Ditiocarb / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D004357:Drug Synergism; D000882:Haplorhini; D006719:Homovanillic Acid / Q000032:analysis; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines; D012642:Selegiline; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D010879:Piperazines; D015102:3,4-Dihydroxyphenylacetic Acid; D012642:Selegiline; D016291:Dizocilpine Maleate; C043425:vanoxerine; D004050:Ditiocarb; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D006719:Homovanillic Acid