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 α-methyl- p-tyrosine (200 mg/kg i.p.) pretreatments. Local infusion of high K + (100 mM) or l-3,4-dihydroxyphenylalanine (L-DOPA, 10 μM) 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 μM), 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 α-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.