MODULATION OF RELEASE OF ACETYLCHOLINE FROM THE STRIATUM BY A PROPOSED EXCITATORY AMINO-ACID ANTAGONIST-U-54494A - COMPARISON WITH KNOWN ANTAGONISTS, DIAZEPAM AND PHENYTOIN

The effect of (U-54494A) cis-3,4-dichloro-N-methyl-N-[2-(1-Pyrrolidinyl)-cyclohexyl] benzamide monohydrochloride, an excitatory amino acid antagonist, on N-methyl-D-aspartic acid (NMDA)- and K+-evoked release of [H-3]acetylcholine ([H-3]ACh) from slices of striatum was investigated. For the purpose of comparison, MK 801, PCP, CGP 37849, CPP, phenytoin and diazepam were investigated under identical conditions. Both U-54494A and the excitatory amino acid antagonists blocked NMDA-evoked release of [H-3]ACh but these compounds failed to inhibit K+-evoked release of this neurotransmitter. Phenytoin blocked both NMDA and K+-evoked release of [H-3]ACh, whereas diazepam was ineffective under similar conditions. These observations indicate that excitatory amino acid antagonists, including U-54494A, may mediate their anticonvulsant effect by blocking the activity of NMDA receptors, diazepam by activating the benzodiazepine receptors and phenytoin by inhibiting the activity of various depolarizing agents.