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 mu M) 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 (d ay 2) after surgery. The dopamine basal value in the striatum was simi lar to 17 fmol/min. Nomifensine (20 mu M) stimulated dopamine release to similar to 170 fmol/min. The increase of dopamine extracellular out put in the striatum after MPP(+) perfusion on day 1 was independent of the concentration of MPP(+) perfused and of the absence or presence o f nomifensine (20 mu M), being similar to 2,500 fmol/ min. The dopamin e basal value in the substantia nigra was below the detection limit of our HPLC equipment. Nomifensine (20 mu M) stimulated dopamine release to similar to 6.3 fmol/min. The increase of dopamine extracellular ou tput 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 nomi fensine on day 1 produced a total protection against MPP(+) (1 mM) per fusion 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 mu M) in the substantia nigra on day 2 was similar to that of MPP(+) (1 m M) in the striatum. The presence of nomifensine (20 mu M) partially pr evented 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 i n the absence or presence of nomifensine on day 2. These results sugge st that terminals in the striatum are more sensitive to the neurotoxic ity of MPP(+) than cell bodies/dendrites in the substantia nigra.