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-carboxyphenylg lycine (S-4CPG) and (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) w ith responses of rat cerebellar Purkinje cells to (1S,3R)-1-aminocyclo pentane- 1,3-dicarboxylic acid (1S,3R-ACPD) were examined by intracell ular recordings in acute cerebellar slices and extracellular recording s in vivo, using multibarrel electrodes. In vitro, both S-4CPG (100 mu M to 1 mM) and MCPG (250 mu M to 1 mM) reversibly and dose-dependentl y reduced an inward current induced by bath-applied 1S,3R-ACPD, an ago nist at metabotropic glutamate receptors (mGluRs), in Purkinje cells v oltage-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 b ut when applied alone also produced an inward current amounting to 26. 8% of that induced by 1S,3R-ACPD. MCPG bath-applied at 250 mu M, 500 m u M, 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 ap plied alone even at a concentration of 1 mM. In vivo, iontophoretic ap plication of 1S,3R-ACPD induced a transient increase followed by a dec rease 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 i n the decreased firing rate was not affected. Our observations demonst rate that both S-4CPG and MCPG antagonize the excitatory response of c erebellar Purkinje cells to 1S,3R-ACPD. The in vitro observations stro ngly suggest that S-4CPG acts as a partial agonist at the metabotropic glutamate receptor mediating the inward current in Purkinje cells whi le MCPG showed no intrinsic activity at concentrations virtually aboli shing the inward current induced by 1S,3R-ACPD. Furthermore, our in vi vo studies indicate that both compounds leave the mechanism resulting in a decreased spontaneous activity of Purkinje cells unaffected, indi cating that both S-4CPG and MCPG might act as antagonists at some but not all members of the mGluR family.