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 agonists and antagonists on noradrenaline (NA)-stimulated [H-3]-cyclic AMP accumul ation were investigated in rat cerebral cortical slices. 2. Quisqualat e (QUIS), L-2-amino-3-phosphonopropionic acid (L-AP3) and glutamate (G LU) elicited concentration-dependent inhibition of (NA)-stimulated [H- 3]-cyclic AMP accumulation, with IC50 values of 105 +/- 29, 275 +/- 36 and 944 +/- 150 mu M respectively. In contrast pha-amino-3-hydroxy-5- methyl-4-isoxazole-propionic acid (AMPA) (0.5 mM) and N-methyl-D-aspar tic acid (NMDA) (0.5 mM) had no effect. 3. (2S,3S,4S)-alpha-(Carboxycy clopropyl)glycine (L-CCGI), 1-Aminocyclo-pentane-1S,3R-dicarbo-xylate (1S,3R-ACPD), ibotenate (IBO) and (RS)-4-carboxy-3-hydroxy-phenylglyci ne (CHPG)elicited a concentration-dependent enhancement of NA-stimulat ed [H-3]-cyclic AMP accumulation, with EC(50) values of 2.5 +/- 0.11, 42 +/- 1.3, 97.8 +/- 2.1 and 157 +/- 13.4 mu M, respectively. 4. (S)-3 -carboxy-4-hydroxyphenylglycine (3C4HPG) and (S)-4-carboxy-3-hydroxyph enyl-glycine (4C3HPG) produced a biphasic effect, at concentrations up to 100 and 500 mu M, respectively, they significantly enhanced the ac tion of NA (100 mu M), at 1mM concentration both compounds as well as alpha-methyl-4-carboxyphenylglycine (MCPG) produced a significant inhi bition of NA-stimulated cyclic AMP accumulation. 5. A putative mGluR a ntagonist - L-AP3, inhibited the 1S,3R-ACPD (100 mu M) induced enhance ment of the action of NA (100 mu M) on [H-3]-cyclic AMP accumulation i n a biphasic manner with an IC50 of 4.5 mu M for the high affinity sit e, which represented 65% of the total and an IC50 of 283 mu M for the low affinity site. 6. beta-adrenoceptor antagonist propranolol inhibit ed the interaction between 1S,3R-ACPD (100 mu M) and NA (100 mu M) on [H-3]-cyclic AMP accumulation by about 80%, with an IC50 of 0.52 +/- 0 .011 mu M, to the level observed after 1S,3R-ACPD alone. Prazosin, an alpha(1)-adrenoceptor antagonist was more potent (IC50 of 0.091 +/- 0. 012 mu M) but less efficacious (60% inhibition) as an inhibitor of the interaction either between NA and 1S,3R-ACPD while yohimbine, na alph a(2)-adrenoceptor antagonist (up to 1 mu M) had no effect. 7. Neither the protein kinase C inhibitor - staurosporine (10 mu M) nor thapsigar gin (1 mu M), which depletes IP3 sensitive calcium stores, inhibited s ignificantly the 1S,3R-ACPD (100 mu M)-induced enhancement of the acti on of NA (100 mu M) on [H-3]-cyclic AMP accumulation. 8. Adenosine dea minase (0.5 U/ml) abolished both the 1S,3R-ACPD (100 mu M)-induced [H- 3]-cyclic AMP accumulation and the synergistic interaction of this com pound with NA (100 mu M). 9. These results indicate the existence of d ifferent subtypes of metabotropic glutamate receptors in rat brain whi ch either inhibit or enhance the NA-stimulated [H-3]-cyclic AMP accumu lation. The enhancement in cerebral cortical slices is mediated via re ceptors which are blocked with high affinity by L-AP3 and occurs via i nteractions with endogenous adenosine; the inhibition is mediated by r eceptors sensitive to quisqualate, L-AP3 and glutamate and may represe nt a predominant interaction between NA and excitatory amino acids (EA A), which in cerebral cortical slices is masked by excitatory effects.