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

1. The effects of agonists of on the evoked N-wave complex in slices of mouse have been studied: most experiments were carried out using slices perfused with Mg(2+)-free solution to which 10 microM 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 mediated component of the potential. The relative agonist potencies were 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 5-250 microM) = quisqualate (5-50 microM) > 1RS,3RS-cis-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 25-1000 microM) > L-glutamate (0.25-2.5 mM); NMDA, alpha-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 microM), sangivamycin (25 microM) and 5-(isoquinolinylsulphonyl)-3-methylpiperazine (50 microM). 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 receptor-mediated component over all stimulus intensities, an effect blocked by the inhibitors of protein kinase C and by S-(+)-AP3 (0.125mM). 4-beta-Phorbol-12,13-diacetate (2.5 muM) also potentiated the component, an action inhibited by protein kinase C inhibitors but not by S-(+)-AP3. IS,3R-ACPD (0.1mM) 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 muM). The K+evoked release of glycine was selectively and significantly increased in the presence 0.1mM 1S,3R-ACPD(antagonized by 0.125 mM S-(+)-AP#) whereas following agonist washout, release of glycine fell to control levels but there was a significant increase in release of aspartate(antagonized by 25 muM sangivamycin and 0.125 muM S-(+)-AP3). It is concluded that mediate (i) a reduction in the latency of the mediated component of potentials by a mechanism that is independent of protein kinase C but which may depend on increased glycine release 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.