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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.

The purpose of this study was to provide further information on the usefulness of N-methyl-D-aspartate (NMDA) discrimination in rats as a behavioral model for NMDA receptor activation. The pharmacological specificity of the NMDA discriminative stimulus was examined in rats trained to discriminate 30 mg/kg, i.p. NMDA from saline using a 2-lever fixed-ratio (FR) 32 food reinforcement schedule. Pharmacologically diverse centrally-acting agents were examined for their ability to substitute for NMDA. Morphine did not substitute for NMDA; neither did the central stimulants, caffeine and (+)-amphetamine, which produced a maximum mean of only 16 and 35% NMDA-lever responding, respectively. Pentylenetetrazol and picrotoxin also did not substitute for NMDA. Compounds interacting with cholinergic neurotransmission including nicotine, physostigmine, arecoline and mecamylamine, produced at best, only intermediate levels of NMDA-lever responding (32-61%), with the highest levels of NMDA-lever responding generally occurring at doses that also reduced rates of responding. These results suggest that the discriminative stimulus properties of NMDA are dissimilar from those of a number of centrally-acting drugs. Combined with the results of studies indicating that the NMDA discriminative stimulus can be antagonized by competitive NMDA antagonists, these results provide further evidence that NMDA receptor activation is the basis of NMDA discrimination and that this model may be useful for studying site-selective NMDA agonists and antagonists.

The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40-60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABAA agonist progabide and its metabolite 4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino)] butyric acid (SL 75102) also partially substituted for PB, producing means of 39-73% PB-lever responding. The GABAB agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABAA agonists, PB and diazepam, although similar to one another, differ from those of direct GABAA receptor agonists, which produced only partial substitution for PB. The GABAB agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.

The discriminative stimulus effects of indirect-acting GABAergic drugs were compared to those of pentobarbital (PB) and midazolam in rats trained to discriminate 5 mg/kg PB from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. PB and midazolam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Valproic acid, an antiepileptic drug and GABA transaminase inhibitor, substituted for PB but not only at a dose that produced response rate suppression. Vigabatrin, an irreversible GABA transaminase inhibitor, failed to substitute for PB, but did produce a dose-dependent decrease in response rates. The GABA uptake inhibitors, 1-[2-[bis[4-(trifluoromethyl)phenyl]- methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (CI-966) and (R(−)-N-[4,4-bis(3-methylthien-2-yl) but-3-enyl] nipecotic acid HCl (tiagabine), produced no greater than 40% PB-lever responding. Aminoxyacetic acid (AOAA), which is described as a nonselective presynaptic GABA agonist, yielded a maximum of 43% PB-lever responding. These results indicate that the discriminative stimulus effects of the indirect GABAA agonists, PB and midazolam, although similar to one another, differ from those of presynaptic GABAergic drugs. Differences in the discriminative stimulus properties of GABA transaminase inhibitors and uptake inhibitors also exist, indicating that not all presynaptic GABA agonists have similar behavioral profiles. These results contribute to a further understanding of the similarities and differences in the behavioral effects of drugs that enhance GABAergic neurotransmission.

Ethanol has been shown to antagonize N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in a number of in vitro systems. Drug discrimination procedures in rats were used to evaluate ethanol as an antagonist of NMDA discrimination and for its ability to produce discriminative stimulus effects similar to those of competitive and noncompetitive NMDA antagonists. Ethanol (300–1500 mg/kg i.p.) failed to antagonize the stimulus effects of 30 mg/kg NMDA, nor did it substitute fully for either the competitive antagonist NPC 12626 nor the noncompetitive antagonist phencyclidine (PCP). A maximum average of 55.4% PCP-lever responding provided evidence for partial substitution in this model. The effects of ethanol on NMDA discrimination are distinct from those previously reported for competitive NMDA antagonists but similar to those of noncompetitive antagonists. On the other hand, ethanol can be distinguished from both competitive and PCP-like noncompetitive NMDA antagonists using drug discrimination procedures.