Phenylglycine derivatives antagonize the excitatory response of Purkinje cells to 1S,3R-ACPD: an in vivo and in vitro study

The interactions of the phenylglycine derivatives (S)-4-carboxyphenylglycine (S-4CPG) and (R,S)-α-methyl-4-carboxyphenylglycine (MCPG) with responses of rat cerebellar Purkinje cells to (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) were examined by intracellular recordings in acute cerebellar slices and extracellular recordings in vivo, using multibarrel electrodes. In vitro, both S-4CPG (100 μM to 1 mM) and MCPG (250 μM to 1 mM) reversibly and dose-dependently reduced an inward current induced by bath-applied 1S,3R-ACPD, an agonist at metabotropic glutamate receptors (mGluRs), in Purkinje cells voltage-clamped at -60 to -65 mV. S-4CPG applied at a concentration of 1 mM reduced the 1S,3R-ACPD induced current to 17% of control values but when applied alone also produced an inward current amounting to 26.8% of that induced by 1S,3R-ACPD. MCPG bath-applied at 250 μM, 500 μM, or 1 mM reduced the 1S,3R-ACPD-induced current to 85%, 56% or 3% of control values, respectively, and did not cause any current when applied alone even at a concentration of 1 mM. In vivo, iontophoretic application of 1S,3R-ACPD induced a transient increase followed by a decrease in the firing rate of Purkinje cells. The excitatory response of Purkinje cells to 1S,3R-ACPD was suppressed during ejection of either one of the phenylglycine derivatives, while the mechanism resulting in the decreased firing rate was not affected. Our observations demonstrate that both S-4CPG and MCPG antagonize the excitatory response of cerebellar Purkinje cells to 1S,3R-ACPD. The in vitro observations strongly suggest that S-4CPG acts as a partial agonist at the metabotropic glutamate receptor mediating the inward current in Purkinje cells while MCPG showed no intrinsic activity at concentrations virtually abolishing the inward current induced by 1S,3R-ACPD. Furthermore, our in vivo studies indicate that both compounds leave the mechanism resulting in a decreased spontaneous activity of Purkinje cells unaffected, indicating that both S-4CPG and MCPG might act as antagonists at some but not all members of the mGluR family.