NMDA receptor antagonists increase the release of dopamine in the substantia nigra of reserpine-treated rats.
Microdialysis of the substantia nigra pars reticulata in freely moving rats disclosed a steady release of dopamine and its metabolites which was greatly reduced after reserpine (4 mg/kg s.c.) and alpha-methyl-p-tyrosine (200 mg/kg i.p.) pretreatments. Local infusion of high K+ (100 mM) or L-3,4-dihydroxyphenylalanine (L-DOPA, 10 microM) significantly increased dialysate levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) in this model. Intranigral application of the non-competitive NMDA receptor antagonist dizocilpine (150 nM), or the competitive NMDA receptor antagonist R-DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate (CGP 40116, 10 microM), via the dialysis probe, did not affect the release of dopamine or its metabolites in intact rats, but further suppressed these releases in reserpine plus alpha-methyl-p-tyrosine-treated animals. When the same amounts of dizocilpine or CGP 40116 were coinfused with L-DOPA, however, they potentiated the recovery of dopamine 12-24 times, and of DOPAC 5-10 times (but not HVA), as well as producing detectable behavioural arousal. The facilitation of dopamine formation from L-DOPA by NMDA receptor antagonists in the substantia nigra pars reticulata could explain the enhancement of L-DOPA's antiparkinsonian activity by these compounds in behavioural experiments.
Department of Pharmacology, School of Pharmacy, London, UK.
C S
CS
Biggs
L J
LJ
Fowler
P S
PS
Whitton
M S
MS
Starr
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012110:Reserpine / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D018759:Adrenergic Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008781:Methyltyrosines; D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D019805:alpha-Methyltyrosine; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine