Neurochemical interactions of competitive N-methyl-D-aspartate antagonists with dopaminergic neurotransmission and the cerebellar cyclic GMP system: functional evidence for a phasic glutamatergic control of the nigrostriatal dopaminergic pathway.
Direct intrastriatal injection of N-methyl-D-aspartate (NMDA; 100 micrograms/rat) increased striatal dopamine (DA) release in vivo. However, parenteral administration of (+/-)-3-(2-carboxypiperizin-4-yl)propyl-1-phosphonic acid (CPP) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) did not alter DA metabolism and release in several brain regions in the rat and mouse. Intracerebroventricular administration of the competitive NMDA antagonists CPP, CGS-19755, 2-amino-5-phosphonopentanoate, and 2-amino-7-phosphonoheptanoate did not alter rat striatal DA metabolism and release but profoundly reduced cerebellar cyclic GMP (cGMP) levels in the same animals. CPP and CGS-19755 decreased basal cerebellar cGMP levels in the mouse with ED50 values of 6 and 1 mg/kg, i.p., respectively. CPP antagonized the harmaline-induced increases in cGMP levels with an ED50 value of 5.0 mg/kg, i.p. CPP (25 mg/kg, i.p.) also decreased basal cGMP levels in mouse cerebellum for up to 3 h, a result suggesting brain bioavailability and a long duration of NMDA receptor antagonism in vivo. These contrasting patterns suggest that NMDA receptors exert a tonic excitatory tone on the guanine nucleotide signal transduction pathway in the cerebellum while exerting a phasic control over nigrostriatal dopaminergic neurotransmission. These results also indicate that competitive NMDA antagonists, unlike phencyclidine receptor agonists, may not mediate biochemical and behavioral effects via dopaminergic mechanisms.
Rao
T S
TS
CNS Diseases Research, G. D. Searle-Monsanto, St. Louis, Missouri 63198.
Cler
J A
JA
Mick
S J
SJ
Emmett
M R
MR
Farah
J M
JM
Contreras
P C
PC
Iyengar
S
S
Wood
P L
PL
D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism*; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000502:physiology*; D005973:Glutamine / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013378:Substantia Nigra / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission
D005973:Glutamine; D016202:N-Methylaspartate; D006152:Cyclic GMP; C001746:3-methoxytyramine; D004298:Dopamine