The enhancement and the inhibition of noradrenaline-induced cyclic AMP accumulation in rat brain by stimulation of metabotropic glutamate receptors.
1. The actions of several metabotropic glutamate receptor and antagonists on noradrenaline (NA)-stimulated [3H]-cyclic AMP accumulation were investigated in rat cerebral cortical slices. 2. Quisqualate (QUIS), L-2-amino-3-phosphonopropionic acid (L-AP3) and glutamate (GLU) elicited concentration-dependent inhibition of (NA)-stimulated [3H]-cyclic AMP accumulation, with IC50 values of 105 +/- 29, 275 +/- 36 and 944 +/- 150 microM respectively. In contrast (Rs)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) (0.5 mM) and N-methyl-D-aspartic acid (NMDA) (0.5 mM) had no effect. 3. (2S,3S,4S)-alpha-(Carboxycyclopropyl)glycine (L-CCGI), 1-Aminocyclo-pentane-1S,3R-dicarbo-xylate (1S,3R-ACPD), ibotenate (IBO) and (RS)-4-carboxy-3-hydroxy-phenylglycine (CHPG)elicited a concentration-dependent enhancement of NA-stimulated [3H]-cyclic AMP accumulation, with EC50 values of 2.5 +/- 0.11, 42 +/- 1.3, 97.8 +/- 2.1 and 157 +/- 13.4 microM, respectively. 4. (S)-3-carboxy-4-hydroxyphenylglycine (3C4HPG) and (S)-4-carboxy-3-hydroxyphenyl-glycine (4C3HPG) produced a biphasic effect, at concentrations up to 100 and 500 microM, respectively, they significantly enhanced the action of NA (100 microM), at 1mM concentration both compounds as well as alpha-methyl-4-carboxyphenylglycine (MCPG) produced a significant inhibition of NA-stimulated cyclic AMP accumulation. 5. A putative mGluR antagonist-L-AP3, inhibited the 1S,3R-ACPD (100 microM) induced enhancement of the action of NA (100 microM) on [3H]-cyclic AMP accumulation in a biphasic manner with an IC50 of 4.5 microM for the high affinity site, which represented 65% of the total and an IC50 of 283 microM for the low affinity site. 6. beta-adrenoceptor antagonist propranolol inhibited the interaction between 1S,3R-ACPD (100 microM) and NA (100 microM) on [3H]-cyclic AMP accumulation by about 80%, with an IC50 of 0.52 +/- 0.011 microM, to the level observed after 1S,3R-ACPD alone. Prazosin, an alpha 1-adrenoceptor antagonist was more potent (IC50 of 0.091 +/- 0.012 microM) but less efficacious (60% inhibition) as an inhibitor of the interaction either between NA and 1S,3R-ACPD while yohimbine, na alpha 2-adrenoceptor antagonist (up to 1 microM) had no effect. 7. Neither the protein kinase C inhibitor - staurosporine (10 microM) nor thapsigargin (1 microM), which depletes IP3 sensitive calcium stores, inhibited significantly the 1S,3R-ACPD (100 microM)-induced enhancement of the action of NA (100 microM) on [3H]-cyclic AMP accumulation. 8. Adenosine deaminase (0.5 U/ml) abolished both the 1S,3R-ACPD (100 microM)-induced [3H]-cyclic AMP accumulation and the synergistic interaction of this compound with NA (100 microM). 9. These results indicate the existence of different subtypes of metabotropic glutamate receptors in rat brain which either inhibit or enhance the NA-stimulated [3H]-cyclic AMP accumulation. The enhancement in cerebral cortical slices is mediated via receptors which are blocked with high affinity by L-AP3 and occurs via interactions with endogenous adenosine; the inhibition is mediated by receptors sensitive to quisqualate, L-AP3 and glutamate and may represent a predominant interaction between NA and excitatory amino acids (EAA), which in cerebral cortical slices is masked by excitatory effects.
Pilc
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Institute of Pharmacology, Polish Academy of Sciences, Krakow, Smetna, Poland.
Legutko
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Czyrak
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D000322:Adrenergic Agonists / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D009498:Neurotoxins / Q000494:pharmacology; D009638:Norepinephrine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D013268:Stimulation, Chemical
D000322:Adrenergic Agonists; D018846:Excitatory Amino Acids; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D000242:Cyclic AMP; D009638:Norepinephrine