Influence of metabotropic glutamate receptor agonists on the inhibitory effects of adenosine A1receptor activation in the rat hippocampus (original) (raw)

1997, British Journal of Pharmacology

Glutamate and other amino acids are the main excitatory neurotransmitters in many brain regions, including the hippocampus, by activating ion channel-coupled glutamate receptors, as well as metabotropic receptors linked to G proteins and second messenger systems. Several conditions which promote the release of glutamate, like frequency stimulation and hypoxia, also lead to an increase in the extracellular levels of the important neuromodulator, adenosine. We studied whether the activation of dierent subgroups of metabotropic glutamate receptors (mGluR) could modify the known inhibitory eects of a selective adenosine A 1 receptor agonist on synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices taken from young (12 ± 14 days old) rats. Stimulation was delivered to the Schaer collateral/commissural ®bres, and evoked ®eld excitatory postsynaptic potentials (fe.p.s.p.) recorded extracellularly from the stratum radiatum in the CA1 area. 2 The concentration-response curve for the inhibitory eects of the selective adenosine A 1 receptor agonist, N 6-cyclopentyladenosine (CPA; 2 ± 50 nM), on the fe.p.s.p. slope (EC 50 =12.5 (9.2 ± 17.3; 95% con®dence intervals)) was displaced to the right by the group I mGluR selective agonist, (R,S)-3,5dihydroxyphenylglycine (DPHG; 10 mM) (EC 50 =27.2 (21.4 ± 34.5) nM, n=4). The attenuation of the inhibitory eect of CPA (10 nM) on the fe.p.s.p. slope by DHPG (10 mM) was blocked in the presence of the mGluR antagonist (which blocks group I and II mGluR), (R,S)-a-methyl-4-carboxyphenylglycine (MCPG; 500 mM). DHPG (10 mM) itself had an inhibitory eect of 20.1+1.9% (n=4) on the fe.p.s.p. slope. 3 The concentration-response curves for the inhibitory eects of CPA (2 ± 20 nM) on the fe.p.s.p. slope were not modi®ed either in the presence of the group II mGluR selective agonist, (2S,3S,4S)-a-(carboxycyclopropyl)glycine (L-CCG-I; 1 mM), or in the presence of the non-selective mGluR agonist (which activates both group I and II mGluR), (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate (ACPD; 100 mM). L-CCG-I had no consistent eects and ACPD (100 mM) decreased by 19.4+1.8% (n=4) the fe.p.s.p. slope. 4 The concentration-response curve for the inhibitory eects of CPA (2 ± 100 nM) on the fe.p.s.p. slope (EC 50 =8.2 (6.9 ± 9.6) nM) was displaced to the right by the group III mGluR selective agonist, L-2amino-4-phosphonobutyrate (L-AP4; 25 mM) (EC 50 =17.7 (13.1 ± 21.9) nM, n=4). The attenuation of the inhibitory eect of CPA (10 nM) on the fe.p.s.p. slope by L-AP4 (25 mM) was blocked in the presence of the mGluR antagonist (selective for the group III mGluR), (R,S)-a-methyl-4-phosphonophenylglycine (MPPG; 200 mM). 5 Both the direct eect of DHPG on synaptic transmission and the attenuation of the inhibitory eect of CPA (10 nM) were prevented in the presence of the protein kinase C selective inhibitors, staurosporine (1 mM) or chelerythrine (5 mM), and thus attributed to activation of protein kinase C. 6 The attenuation by L-AP4 (25 mM) of the inhibitory eect of CPA (10 nM) on the fe.p.s.p. slope was also prevented by the protein kinase C selective inhibitors, staurosporine (1 mM) or chelerythrine (5 mM), and thus attributed to activation of protein kinase C. But this eect seemed to be distinct from the direct eect of L-AP4 (25 mM) on synaptic transmission, which was not modi®ed by the protein kinase C selective inhibitors. 7 We conclude that agonists of metabotropic glutamate receptors (Groups I and III) are able to attenuate the inhibitory eects of adenosine A 1 receptor activation in the hippocampus. This interaction may have pathophysiological relevance in hypoxia, in which there is marked release of both excitatory amino acids and the important endogenous neuroprotective substance, adenosine.