Responsiveness of striatal dopamine release in awake animals after chronic 1-methyl-4-phenylpyridinium ion-induced lesions of the substantia nigra.
Extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid were measured by microdialysis in rat striatum 1 month after a unilateral infusion via a dialysis probe of a high concentration (10 mM) of 1-methyl-4-phenylpyridinium ion (MPP+) into the substantia nigra. The basal extracellular DA concentration at the lesioned side was about 20% of the concentration at the nonlesioned side. However, basal DOPAC dialysate levels from the lesioned striatum represented only 2.4% of those from the contralateral side. Intrastriatal infusion with nomifensine increased the dialysate content of DA about twofold and eightfold at the lesioned and nonlesioned sides, respectively. Co-infusion of nomifensine with (-)-sulpiride caused an additional pronounced rise of the DA output on top of the nomifensine-induced increase at the nonlesioned side, whereas no effect was observed at the lesioned side. Finally, MPP+ (10 mM) was infused for 45 min into both striata. The increase in the dialysate content of DA in response to MPP+ (considered as an index of the total striatal DA content) from the lesioned side was only 0.6% of the MPP(+)-induced DA increase from the nonlesioned side. A strong compensatory response to increased extracellular dopamine was observed in the ipsilateral striatum. This effect was achieved by a severe suppression of reuptake mechanisms, as well as of the autoreceptor feedback response. It is concluded that infusion of MPP+ into the substantia nigra can be used as a chronic biochemical model for clinically manifest parkinsonism.
Santiago
M
M
Department of Medicinal Chemistry, University Centre for Pharmacy, Groningen, The Netherlands.
Westerink
B H
BH
Rollema
H
H
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D008297:Male; D009627:Nomifensine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D013469:Sulpiride / Q000494:pharmacology; D013997:Time Factors; D014851:Wakefulness
D009627:Nomifensine; D013469:Sulpiride; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine