DISCRIMINATIVE STIMULUS EFFECTS OF EXCITATORY AMINO-ACID AGONISTS IN RATS

Sixteen male Sprague-Dawley rats were trained to discriminate 30 mg/kg i.p. NMDA from saline using a 2-lever operant procedure. Responding w as maintained under a FR 32 schedule of food reinforcement. Substituti on tests were completed with NMDA (3-56 mg/kg) and other putative exci tatory amino acids, L-glutamate (30-560 mg/kg), L-aspartate (30-300 mg /kg), L-homocysteic acid (100-1500 mg/kg), L-cysteine (30-1000 mg/kg), monosodium glutamate (100-3000 mg/kg), kainic acid (0.1-3 mg/kg) and the selective NMDA receptor agonist, D,L-(tetrazol-5-yl)glycine (LY 28 5265) (0.01-1.0 mg/kg). LY 285265 fully substituted for NMDA and was a pprox 100-fold more potent than NMDA for producing NMDA-like discrimin ative stimulus effects. Partial substitution occurred with monosodium glutamate, L-glutamate and L-homocysteic acid, resulting in mean maxim um levels of 49-59% NMDA-lever responding, however response rate decre ases were only obtained with 3000 mg/kg monosodium glutamate, suggesti ng that behaviorally active doses of the other compounds may not have been fully studied. L-Cysteine, kainic acid and L-aspartate failed to substitute for NMDA or produce decreases in response rates. Unlike wit h other excitatory agonists tested, full substitution occurred only wi th LY 285265, providing evidence that selective NMDA receptor activati on is the basis for the NMDA discriminative stimulus. These results al so suggest that LY 285265 is a potent, systemically active, selective agonist for the NMDA receptor.