Nigral and striatal comparative study of the neurotoxic action of 1-methyl-4-phenylpyridinium ion: involvement of dopamine uptake system.
Microdialysis was used in a comparative study of the neurotoxic action of MPP+ in the absence or presence of nomifensine (20 microM) in the striatum and substantia nigra. Three different concentrations of MPP+ (1, 2.5, and 5 mM) were perfused for 15 min at 24 (day 1) and 48 h (day 2) after surgery. The dopamine basal value in the striatum was approximately 17 fmol/min. Nomifensine (20 microM) stimulated dopamine release to approximately 170 fmol/min. The increase of dopamine extracellular output in the striatum after MPP+ perfusion on day 1 was independent of the concentration of MPP+ perfused and of the absence or presence of nomifensine (20 microM), being approximately 2,500 fmol/ min. The dopamine basal value in the substantia nigra was below the detection limit of our HPLC equipment. Nomifensine (20 microM) stimulated dopamine release to approximately 6.3 fmol/min. The increase of dopamine extracellular output in the substantia nigra was MPP+ dose-dependent (1 mM, 75 fmol/min; 2.5 mM, 150 fmol/min; and 5 mM, 250 fmol/min) and independent of the presence or absence of nomifensine. On day 2, the presence of nomifensine on day 1 produced a total protection against MPP+ (1 mM) perfusion in the striatum, which was not observed against MPP+ (5 mM). MPP+ (1 mM) did not produce any neurotoxic action in the substantia in the absence or presence of nomifensine. The MPP+ (2.5 mM) effect on dopamine extracellular output in the absence of nomifensine (20 microM) in the substantia nigra on day 2 was similar to that of MPP+ (1 mM) in the striatum. The presence of nomifensine (20 microM) partially prevented the neurotoxic effect of MPP+ (2.5 mM) on dopaminergic cell bodies/ dendrites in the substantia nigra. The MPP+ (5 mM) effect on dopamine extracellular output was similar in both structures studied in the absence or presence of nomifensine on day 2. These results suggest that terminals in the striatum are more sensitive to the neurotoxicity of MPP+ then cell bodies/dendrites in the substantia nigra.
Santiago
M
M
Departamento de Bioquimica, Facultad de Farmacia, Sevilla, Spain.
Machado
A
A
Cano
J
J
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D009627:Nomifensine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects*
D018765:Dopamine Uptake Inhibitors; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D009627:Nomifensine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine