Behavioral pharmacological profile of CGS 19755, a competitive antagonist at N-methyl-D-aspartate receptors

Abstract

CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid), a competitive antagonist at N-methyl-D-aspartate (NMDA)-preferring receptors, blocked both NMDA-induced convulsions in normal CF1 mice and sound-induced wild running in seizure-prone DBA/2 mice. The ED50 values for CGS 19755 to produce these effects (in the range of 2 mg/kg i.p.) were at least 3-fold lower than those which impaired the traction reflex, an index of motor coordination. When administered p.o. by gavage, CGS 19755 had little or no effect in these test procedures. In an experimental model of anxiety in rats, CGS 19755 significantly increased conflict responding within a relatively narrow dose range (minimum effective dose, 1.73 mg/kg i.p.). At higher doses of CGS 19755, this effect appeared to be obscured by drug-induced reductions in overall responding. Potential muscle relaxant effects were also suggested by the generalization of CGS 19755 to diazepam discriminative stimuli (ED50 = 9.0 mg/kg i.p.) and by impaired rotorod performance (ED50 = 6.2 mg/kg i.p.) in rats. Although some resemblances were apparent between the behavioral effects of CGS 19755 and those of phencyclidine-type drugs, the phencyclidine-like behaviors appeared only at considerably higher doses of CGS 19755 than those associated with anticonflict activity, and only partial generalization of CGS 19755 to dexoxadrol was observed at high doses. CGS 19755 promises to be an important new research tool for investigating the function of brain NMDA receptors.