PHARMACOLOGICAL ANTAGONISM OF THE ACTIONS OF GROUP-II AND GROUP-III MGLUR AGONISTS IN THE LATERAL PERFORANT PATH OF RAT HIPPOCAMPAL SLICES

1 An understanding of the physiological and pathological roles of meta botropic glutamate receptors (mGluRs) is currently hampered by the lac k of selective antagonists. Standard extracellular recording technique s were used to investigate the activity of recently reported mGluR ant agonists on agonist induced depressions of synaptic transmission in th e lateral perforant path of hippocampal slices obtained from 12-16 day -old rats. 2 The group III specific mGluR agonist, (S)-2-amino-4-phosp honobutanoate (L-AP4) depressed basal synaptic transmission in a rever sible and dose-dependent manner. The mean (+/-s.e.mean) depression obt ained 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 (D CG-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 mea n depression obtained with 1 mu M DCG-IV was 73+/-7% and the IC50 valu e 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 mGlu R 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-tetrazoly lphenylglycine (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, bu t analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L-AP4-induced effects. 6 T he most effective antagonist tested against 10 mu M L-AP4 was MPPG (me an 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 va lues 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 aden osine receptor agonist, 2-chloroadenosine (500 nM; n=3). 7 We conclude that both group II and group III mGluRs can mediate synaptic depressi ons induced by mGluR agonists in the lateral perforant path. The mGluR antagonists MTPG, MPPG and MAP4 should be useful in determining the r oles of group II and III mGluRs in the central nervous system.