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

Abstract

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. 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 μm L‐AP4 (the maximum concentration tested) was 74 ± 3% and the IC50 value was 3 ± 1 μm (n = 5). 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 μm (1S,3S)‐ACPD was 83 ± 8% and the IC50 value was 12 ± 3 μm (n = 5). The mean depression obtained with 1 μm DCG‐IV was 73 ± 7% and the IC50 value was 88 ± 15 nM (n = 4). Synaptic depressions induced by the actions of 20 μm (1S,3S)‐ACPD and 10 μm L‐AP4 were antagonized by the mGluR antagonists, (+)‐α‐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)‐α‐methyl‐4‐tetrazolylphenylglycine (MTPG), (RS)‐α‐methyl‐4‐sulphonophenylglycine (MSPG) and (RS)‐α‐methyl‐4‐phosphonophenylglycine (MPPG) (all tested at 500 μm). (+)‐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. The most effective antagonist tested against 10 μm L‐AP4 was MPPG (mean reversal 90 ± 3%; n = 4). In contrast, the most effective antagonist tested against 20 μm (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 KD values of 11.7 μm and 27.5 μm, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2‐chloroadenosine (500 nM; n = 3). 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.

Group II and III Metabotropic Glutamate Receptors Suppress Excitatory Synaptic Transmission in the Dorsolateral Bed Nucleus of the Stria Terminalis

“…Consistent with the function of group II mGluRs in other brain regions (Bushell et al, 1996;Macek et al, 1996;Kilbride et al, 1998), we find selective activation of group II mGluRs in the BNST can produce a reversible depression of synaptic transmission. We find that two group II mGluR selective agonists, DCG-IV and LY354740 (Schoepp et al, 1997), inhibited glutamate-dependent field potentials and EPSCs, and that this effect was blocked by LY341495 at concentrations selective for group II mGluRs.…”

Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergic Neurons in the Hippocampus

“…These alterations point to an abnormal hippocampal function that, besides a reduced presynaptic control of glutamate release from the lateral perforant path onto granule cells (Bushell et al, 1996;Shigemoto et al, 1997;Zhai et al, 2002), will also result in altered temporal patterns of GABA release from interneurons. Figure 12.…”

Knock-In Mice Lacking the PDZ-Ligand Motif of mGluR7a Show Impaired PKC-Dependent Autoinhibition of Glutamate Release, Spatial Working Memory Deficits, and Increased Susceptibility to Pentylenetetrazol

“…The mGluR7 subtype is the most prominent member of the group III mGluR subfamily found on presynaptic terminals in different brain regions (Bradley et al, 1996;Kinoshita et al, 1998). It provides neurons with a negative feedback mechanism which, by inhibiting voltage-dependent Ca 2ϩ channels, reduces glutamate release (Bushell et al, 1996;Perroy et al, 2000;Millan et al, 2002). Because of its low affinity for glutamate, mGluR7 has been proposed to only be activated under conditions of sustained synaptic activity (Okamoto et al, 1994).…”