PHARMACOLOGY OF METABOTROPIC GLUTAMATE RECEPTOR-MEDIATED ENHANCEMENT OF RESPONSES TO EXCITATORY AND INHIBITORY AMINO-ACIDS ON RAT SPINAL NEURONS IN-VIVO

Using the technique of microelectrophoresis on spinal neurones in pent obarbitone-anaesthetized rats, (1S,3R)-1-aminocyclo-pentane-1,3-dicarb oxylate (1S,3R-ACPD) reversibly and dose-dependently enhanced response s to pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainat e, N-methyl-D-aspartate (NMDA) and L-glutamate to a similar extent. 1S ,3R-ACPD also enhanced inhibitory responses to both glycine and gamma- aminobutyrate (GABA). Such results are consistent with a metabotropic glutamate receptor-mediated decrease in membrane conductance. 1S,3R-AC PD was the most active metabotropic agonist tested for these effects; the rank order of activity was: 1S,3R-ACPD greater than or equal to (2 S,3S,4S)alpha-(carboxycyclopropyl)-glycine(L - CCG - 1) > (R,S)-3,5-di hydroxy-phenylglycine (3,5 - DHPG) > (S)-homoquisqualate > quisqualate = 1S,3S-ACPD > L-2-amino-4-phosphonobutyrate (L-AP4)> 1R,3S-ACPD. The se effects of 1 S,3R-ACPD were antagonized by (RS)-alpha-methyl-4-carb oxy-phenylglycine (M4CPG) and (S)-4-carboxy-3-hydroxy-phenylglycine (4 C3HPG) but not by (S)-4-carboxy-phenylglycine (4CPG) or L-amino-3-phos phono-propionate (L-AP3). The pharmacology of the actions of mGluR ago nists and antagonists on rat spinal neurones in vivo does not obviousl y correlate with the published pharmacology of a single cloned metabot ropic glutamate receptor subtype but rather suggests that bath Group 1 and 2 receptors contribute to the above effects.