Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices

1 An understanding of the physiological and pathological roles of metabotropic glutamate receptors (mGluRs) is currently hampered by the lack of selective antagonists. Standard extracellular recording techniques were used to investigate the activity of recently reported mGluR antagonists on agonist induced depressions of synaptic transmission in the lateral perforant path of hippocampal slices obtained from 12-16 day-old rats. 2 The group III specific mGluR agonist, (S)-2-amino-4-phosphonobutanoate (L-AP4) depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean (+/-s.e.mean) depression obtained with 100 mu M L-AP4 (the maximum concentration tested) was 74+/-3% and the IC50 value was 3 +/- 1 mu M (n=5). 3 The selective group II mGluR agonists, (1S,3S)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3S)-ACPD) and (2S, 1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) also depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean depression obtained with 200 mu M (1S,3S)-ACPD was 83+/-8% and the IC50 value was 12+/-3 mu M (n=5). The mean depression obtained with 1 mu M DCG-IV was 73+/-7% and the IC50 value was 88+/-15 nM (n=4). 4 Synaptic depressions induced by the actions of 20 mu M (1S,3S)-ACPD and 10 mu M L-AP4 were antagonized by the mGluR antagonists, (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4), (2S, 1'S,2'S)-2-methyl-2-(2'-carboxycyclopropyl)glycine (MCCG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) (all tested at 500 mu M). 5 (+)-MCPG was a weak antagonist of both L-AP4 and (1S,3S)-ACPD-induced depressions. MCCG was selective towards (1S,3S)-ACPD, but analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L-AP4-induced effects. 6 The most effective antagonist tested against 10 mu M L-AP4 was MPPG (mean reversal 90+/-3%; n=4). In contrast, the most effective antagonist tested against 20 mu m (1S,3S)-ACPD induced depressions was MTPG (mean reversal 64+/-4%; n=4). Both antagonists produced parallel shifts in agonist dose-response curves. Schild analysis yielded estimated K-D values of 11.7 mu M and 27.5 mu M, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2-chloroadenosine (500 nM; n=3). 7 We conclude that both group II and group III mGluRs can mediate synaptic depressions induced by mGluR agonists in the lateral perforant path. The mGluR antagonists MTPG, MPPG and MAP4 should be useful in determining the roles of group II and III mGluRs in the central nervous system.