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Background and purpose: Specific and selective inhibitors for mGlu1 receptors are presently inadequate. A new generation of non-competitive mGlu1 antagonists with low nanomolar potencies is emerging. We evaluated two new compounds, YM-298198 and JNJ16259685, for effectiveness, potency and specificity for the first time in a brain slice preparation. Experimental approach: Patch-clamp recording of Purkinje neurones in cerebellar slices were obtained. The slow mGlu1mediated EPSP was used to establish a concentration-response curve. Fast excitatory synaptic inputs were tested for nonspecific effects. Key results: YM-298198 and JNJ16259685 inhibited the synaptic activation of mGlu1 in a concentration-dependent manner (IC50 values of 24 nM and 19 nM, respectively). The antagonists were slow to inhibit and to reverse on washout, probably due to their lipophilic nature. There were no non-specific effects on fast AMPA receptor-mediated synaptic transmission in the cerebellum. Conclusions and implications: These compounds are more than a thousand-fold more potent than previously available compounds. Their selectivity and specificity will be very useful for studying the role of mGlu1 receptors both in vitro and in vivo. British Journal of Pharmacology (2007) 151, 870–876; doi:10.1038/sj.bjp.0707286; published online 14 May 2007

Metabotropic glutamate (mGlu) receptors are located pre- and postsynaptically at central synapses. Activation of the receptors by exogenous agonists usually results in a reversible depression of fast glutamatergic neurotransmission. Evidence that synaptically released glutamate has such an action, however, is scarce. Sharp microelectrode recordings were used to investigate the modulatory role of mGlu receptors at a well-studied glutamatergic synapse, the one between parallel fibres and Purkinje cells in rat cerebellar slices. Brief, tetanic stimulation of the parallel fibres caused a depression of subsequent fast EPSPs. This posttetanic depression (PTD) reached its maximum 4.5 s after the tetanus. Measured at this point, PTD was frequency-dependent; 10 stimuli at 20 Hz produced no significant depression, whereas, at 100 Hz the same number of stimuli was maximally effective (~50% depression). The nonselective mGlu antagonist, (S)-a-methyl-4-carboxyphenylglycine 1 mM or the GABAB antagonist, CGP35348 (1 mM), both decreased the magnitude of the PTD. In the presence of CGP35348 the mGlu1 antagonist, 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (300 mM), inhibited PTD further. A group II/III mGlu antagonist had no effect. These observations indicate that synaptically activated mGlu1 receptors not only generate a slow EPSP and induce Ca 2+ mobilization in Purkinje cells, as reported previously, but also produce a transient depression of fast synaptic transmission. This short-term plasticity may be important for shaping the output of cerebellar circuits and/or it could provide a substrate for long-term depression when additional mechanisms are superimposed.