Differential effects of intrastriatal and intranigral injections of glutamate antagonists on motor behaviour in the reserpine-treated rat.
A variety of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonists, and the antiepileptic drug lamotrigine, were examined for their ability to restore locomotion and other behaviours when injected stereotaxically via indwelling cannulae into the striatum or substantia nigra pars reticulata of rats rendered akinetic with reserpine (5 mg/kg i.p. 24 h beforehand). Only the competitive N-methyl-D-aspartate antagonists 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate and R-DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate stimulated locomotion from the striatum, whereas 2-amino-phosphonopentanoic acid, the N-methyl-D-aspartate channel blockers dizocilpine maleate and phencyclidine, and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione, were additionally effective in the substantia nigra pars reticulata. The N-methyl-D-aspartate glycine site antagonist (RS)-3-amino-1-hydroxypyrrolidin-2-one and the glutamate release inhibitor lamotrigine failed to restore locomotion at these sites, and the N-methyl-D-aspartate polyamine site antagonist eliprodil was ineffective in the substantia nigra pars reticulata, although all compounds tested (except lamotrigine) induced orofacial, head and/or limb movements to some degree. Except for 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione, locomotion was accompanied dose-dependently by increasingly pronounced ataxia and postural abnormalities. These results show that the monoamine-depleted substantia nigra pars reticulata has a broader spectrum of responsitivity to the antiparkinsonian actions of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid antagonists than does the striatum, and that the harmful as well as the beneficial effects of these compounds on locomotion arise from these two structures.
Kaur
S
S
Department of Pharmacology, School of Pharmacy, London, U.K.
Starr
M S
MS
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000502:physiology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000494:pharmacology*; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012110:Reserpine