1 Group III metabotropic glutamate receptors (mGluRs) of the subtype 4a are localized within presynaptic active zones of cerebellar parallel ®bre (PF)-Purkinje cell (PC) synapses. In order to investigate the conditions necessary for group III mGluR autoreceptor-activation by synaptically released glutamate, we characterized the e ects of selective agonists and antagonists on excitatory postsynaptic currents (EPSCs) evoked by several distinct PF stimulation patterns. 2 The group III mGluR-selective agonist L-AP4 depressed evoked EPSCs at PF-PC synapses in rat brain slices with an EC 50 of 2.4 mM and maximum inhibition of 80%. This L-AP4-induced depression was antagonized by the group III mGluR-selective antagonist MSOP with an estimated equilibrium dissaciation constant of 12.5 mM. 3 Paired-pulse or four-pulse PF stimulations did not activate presynaptic group III mGluRs as revealed by the lack of e ect of 1 mM MSOP on relative test EPSC amplitudes with latencies of 250 ± 500 ms. The potentiation of a test EPSC evoked 200 ± 500 ms after a short tetanic burst (100 Hz for 60 ms), was also unchanged in the presence of MSOP. 4 Endogenous autoreceptor-activation was revealed only during prolonged stimulation trains (10 Hz for 4.4 s), where, in the presence of 1 mM MSOP, the EPSC amplitudes were enhanced by 15%. 5 These observations support an autoreceptor function of group III mGluRs and a role in shortterm synaptic plasticity at PF synapses. However, the low to moderate activation levels observed, despite the close spatial relation with glutamate release sites, suggests that additional mechanisms regulate receptor activation.

The distribution and abundance of specific binding sites (=95% of total) in sections of rat CNS, revealed by quantitative receptor radioautography and image analysis, indicated a very discrete localization. Highest binding values were observed in cortical layers (binding in layers 1 and 2> binding in layers 3-6), hippocampal formation, striatum, dorsal septum, reticular thalamic nucleus, cerebellar molecular layer, and spinal cord dorsal horn. At 1 nM, the values for specific binding were highest in the cortical layers 1 and 2 and lowest in the brainstem (=2.6 and 0.4 pmol/mg of protein, respectively). Ro 48-8587 is a potent and selective AMPA receptor antagonist with improved binding characteristics (higher affinity, selectivity, and specific binding) compared with those previously reported. Key Words: a-Amino-3-hydroxy-5-methylisoxazole-4-propionate-9-lmidazol-1 -yl-8-nitro-2,3, 5,6-tetrahydro- High-affinity a-aniino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are ligand-gated cation channels for L-glutalnate, the major excitatory transmitter in the mammalian CNS. Their activation mediates fast transmission at glutamatergic synapses. The receptors, heterooligomeric proteins composed of the subunits G1uR1 -4 with flip and flop forms (Hollmann and Heinemann, 1994;Bettler and Mulle, 1995;Barnard, 1997), play key roles in CNS physiology and pathology. AMPA receptor subunits G1uR1 -4 are differentially regulated during ontogeny, and in adult rat brain they have only partially overlapping distributions (Keinanen et al

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