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 was maintained under a FR 32 schedule of food reinforcement. Substitution tests were completed with NMDA (3-56 mg/kg) and other putative excitatory 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 285265) (0.01-1.0 mg/kg). LY 285265 fully substituted for NMDA and was approx 100-fold more potent than NMDA for producing NMDA-like discriminative stimulus effects. Partial substitution occurred with monosodium glutamate, L-glutamate and L-homocysteic acid, resulting in mean maximum levels of 49-59% NMDA-lever responding, however response rate decreases were only obtained with 3000 mg/kg monosodium glutamate, suggesting 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 with other excitatory agonists tested, full substitution occurred only with LY 285265, providing evidence that selective NMDA receptor activation is the basis for the NMDA discriminative stimulus. These results also suggest that LY 285265 is a potent, systemically active, selective agonist for the NMDA receptor.