Actions of agonists of metabotropic glutamate receptors on synaptic transmission and transmitter release in the olfactory cortex

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Abstract
1 The effects of agonists of metabotropic glutamate receptors on the evoked N-wave complex in slices of mouse olfactory cortex have been studied: most experiments were carried out using slices perfused with Mg2+-free solution to which 10 μm of either 6,7-dinitroquinoxaline-2,3-dione or 6-cyano-7-nitroquinoxaline-2,3-dione was applied. 2 Following agonist washout, a slowly developing, long lasting potentiation of the complex occurred which was confined to the N-methyl-d-aspartate (NMDA) receptor-mediated component of the potential. The relative agonist potencies were 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 5–250 μm) = quisqualate (5–50 μm) > 1RS,3RS-cis-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 25–1000 μm) > l-glutamate (0.25–2.5 mm); NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and l-aspartate were inactive. 3 Potentiation of the NMDA receptor-mediated component by 1S,3R-ACPD (0.1 mm) was non-competitively antagonised by S-(+)- but not R-(−)-2-amino-3-phosphonopropionate (AP3, 0.125 mm), equally by d-(−) and l-(+)-2-amino-4-phosphonobutyrate (0.25 mm) and also by the protein kinase C inhibitors sphingosine, (25 μm), sangivamycin (25 μm) and 5-(isoquinolinylsulphonyl)-3-methylpiperazine (50 μm). 4 In a series of input-output experiments, 1S,3R-ACPD (0.1 mm) reversibly reduced the latency to peak of the NMDA receptor-mediated component at submaximal stimulus intensities, an effect blocked by S-(+)-AP3 (0.125 mm). On agonist washout, there was an increase in the area of the NMDA receptor-mediated component over all stimulus intensities, an effect blocked by the inhibitors of protein kinase C and by S-(+)-AP3 (0.125 mm). 4-β-Phorbol-12,13-diacetate (2.5 μm) also potentiated the component, an action inhibited by protein kinase C inhibitors but not by S-(+)-AP3. 5 1S,3R-ACPD (0.1 mm) had no significant effect on postsynaptic responses evoked by NMDA, AMPA and kainate, but significantly reversed a partial antagonism of NMDA responses produced by 7-chlorokynurenate (2.5 μm). 6 The K+-evoked release of glycine was selectively and significantly increased in the presence of 0.1 mm 1S,3R-ACPD (antagonized by 0.125 mm S-(+)-AP3) whereas following agonist washout, release of glycine fell to control levels but there was a significant increase in release of aspartate (antagonized by 25 μm sangivamycin and 0.125 mm S-(+)-AP3). 7 It is concluded that metabotropic glutamate receptors mediate (i) a reduction in the latency of the NMDA receptor-mediated component of potentials by a mechanism that is independent of protein kinase C but which may depend on increased glycine release and (ii) a long lasting increase in the total area of the potential by increasing transmitter (possibly aspartate) release by a mechanism that is protein kinase C-dependent.

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