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Excitatory Amino Acid Receptors Coupled to the Nitric Oxide/Cyclic GMP Pathway in Rat Cerebellum During Development
Author(s) -
Southam E.,
East S. J.,
Garthwaite J.
Publication year - 1991
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1991.tb03468.x
Subject(s) - nmda receptor , ampa receptor , glutamate receptor , cnqx , kainate receptor , chemistry , cerebellum , ionotropic effect , nitric oxide , excitatory amino acid antagonists , 2 amino 5 phosphonovalerate , excitatory postsynaptic potential , receptor , medicine , biochemistry , endocrinology , biology
The coupling of excitatory amino acid receptors to the formation of nitric oxide (NO) from arginine during the postnatal development of rat cerebellum was assayed in slice preparations by measuring cyclic GMP accumulation. In the immature tissue, N ‐methyl‐D‐aspartate (NMDA) and glutamate were highly efficacious agonists, whereas α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) and quisqualate evoked only small responses. The effect of glutamate at all concentrations tested (up to 10 m M ) was abolished by the NMDA antagonist, (+)‐5‐methyl‐10,11‐dihydro‐5 H ‐dibenzo[ a,d ]cyclohepten‐5,10‐imine maleate (MK‐801). In adult slices, AMPA and quisqualate were much more effective and their effects were inhibited by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione, an antagonist for ionotropic non‐NMDA receptors, whereas the apparent efficacy of NMDA was greatly reduced. The major changes took place between 8 and 14 days postnatum and, in the case of NMDA, part of the loss of sensitivity appeared to reflect a decline in the ambient levels of glycine with age. Moreover, a component of the response to glutamate in the adult was resistant to MK‐801. Cyclic GMP accumulations induced by NMDA and non‐NMDA agonists alike were Ca 2+ ‐dependent and could be antagonized by competitive NO synthase inhibitors in an arginine‐sensitive manner, indicating that they are all mediated by NO formation. With one of the inhibitors, L‐N G ‐nitroarginine, a highly potent component (IC 50 = 6 n M ) evident in slices from rats of up to 8 days old was lost during maturation, indicating that there may be a NO synthase isoform which is prominent only in the immature tissue. Cyclic GMP levels in adult slices under “basal” conditions were reduced markedly by blocking NMDA receptors, by inhibiting action potentials with tetrodotoxin, or by NO synthase inhibition, suggesting that the endogenous transmitter released during spontaneous synaptic activity acts mainly through NMDA receptors to trigger NO formation.