A review of in vivo modulation of cerebellar cGMP levels by excitatory amino acid receptors: role of NMDA, quisqualate and kainate subtypes.
1. Agonists of all three EAA receptor subtypes augment cerebellar cGMP levels in vivo. 2. Agonists of the NMDA-associated glycine receptor also increase cerebellar cGMP levels but with lesser efficacy than EAA agonists. 3. Pharmacological agents, such as harmaline and pentylenetetrazol, which enhance endogenous EAA transmission also increase cerebellar cGMP levels in vivo. 4. Increases in cerebellar cGMP elicited by EAA receptor agonists are blocked by inhibition of nitric oxide synthase with N-monomethyl-L-arginine. 5. Basal cerebellar cGMP levels are decreased in a dose-dependent manner by competitive and non-competitive NMDA receptor antagonists but not by blockade of the NMDA-associated glycine receptor. 6. Selective alpha-1 blockade also antagonizes the actions of NMDA-dependent increases in cerebellar cGMP, suggesting NMDA receptor modulation of NE release from noradrenergic mossy fibers. 7. Quisqualate-dependent increases in cerebellar cGMP were blocked by the nonselective EAA antagonist, DNQX, but not by glycine antagonists or noncompetitive NMDA antagonists. 8. The sigma ligands, ifenprodil and BMY 14802, which did not alter or increased basal cerebellar cGMP levels, respectively, antagonized NMDA-dependent increases in cGMP levels. 9. The polyamines, spermine and spermidine, also did not change basal cGMP levels but nonselectively antagonized EAA-mediated increases in cGMP. 10. In summary, all 3 major EAA subtypes appear to modulate cerebellar cGMP levels in vivo. These actions also involve the intermediate generation of nitric oxide. The NMDA receptor population also appears to reside mainly on noradrenergic nerve endings in the cerebellum.
Wood
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Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ.
Rao
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D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006801:Humans; D018091:Receptors, AMPA; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D006152:Cyclic GMP; D018091:Receptors, AMPA; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter