Katherine L Nicholson1, Robert L Balster. 1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA. klnichol@vcu.edu
Abstract
RATIONALE: Many N-methyl-D-aspartate (NMDA) antagonists produce phencyclidine (PCP)-like side effects that limit their clinical utility. NMDA glycine-site antagonists may be less likely to produce these effects than other site-selective NMDA antagonists. OBJECTIVES: The objective of the study is to compare the discriminative stimulus effects of novel NMDA glycine-site drugs to those of channel blocking and competitive NMDA antagonists. MATERIALS AND METHODS: Drug discrimination studies were performed in separate groups of rats trained with saline vs. PCP (2 mg/kg i.p.) or the competitive antagonist NPC 17742 (4 mg/kg i.p.) using a standard two-lever operant conditioning procedure under an FR32. RESULTS: Neither the partial glycine-site agonists aminocyclopropane carboxylic acid methyl ester and (+)-HA-966 nor the antagonists L701,324; MDL 100,458; MDL 100,748; MDL 103,371; MDL 104,472; MDL 105,519; MRZ 2/571; MRZ 2/576; and ACEA 0762 produced >50% PCP-lever selection, though all were tested over a sufficient dose range to produce response rate decreasing effects. All of the antagonists, except MDL 100,458 and MDL 100,748, were also tested for NPC 17742-like effects, producing somewhat more variable results than in PCP-trained rats. ACEA-0762 produced full substitution for NPC 17742, whereas MDL 105,519 produced no substitution. The remaining compounds engendered between 20% and 80% drug-lever selection. CONCLUSION: These results provide evidence that NMDA glycine-site partial agonists and antagonists generally do not produce discriminative stimulus effects similar to those of representative NMDA channel blockers or competitive antagonists. This suggests that these NMDA glycine-site antagonists should be less likely to produce the undesirable behavioral side effects seen in clinical trials with many other NMDA antagonists.
RATIONALE: Many N-methyl-D-aspartate (NMDA) antagonists produce phencyclidine (PCP)-like side effects that limit their clinical utility. NMDA glycine-site antagonists may be less likely to produce these effects than other site-selective NMDA antagonists. OBJECTIVES: The objective of the study is to compare the discriminative stimulus effects of novel NMDA glycine-site drugs to those of channel blocking and competitive NMDA antagonists. MATERIALS AND METHODS: Drug discrimination studies were performed in separate groups of rats trained with saline vs. PCP (2 mg/kg i.p.) or the competitive antagonist NPC 17742 (4 mg/kg i.p.) using a standard two-lever operant conditioning procedure under an FR32. RESULTS: Neither the partial glycine-site agonists aminocyclopropane carboxylic acid methyl ester and (+)-HA-966 nor the antagonists L701,324; MDL 100,458; MDL 100,748; MDL 103,371; MDL 104,472; MDL 105,519; MRZ 2/571; MRZ 2/576; and ACEA 0762 produced >50% PCP-lever selection, though all were tested over a sufficient dose range to produce response rate decreasing effects. All of the antagonists, except MDL 100,458 and MDL 100,748, were also tested for NPC 17742-like effects, producing somewhat more variable results than in PCP-trained rats. ACEA-0762 produced full substitution for NPC 17742, whereas MDL 105,519 produced no substitution. The remaining compounds engendered between 20% and 80% drug-lever selection. CONCLUSION: These results provide evidence that NMDA glycine-site partial agonists and antagonists generally do not produce discriminative stimulus effects similar to those of representative NMDA channel blockers or competitive antagonists. This suggests that these NMDA glycine-site antagonists should be less likely to produce the undesirable behavioral side effects seen in clinical trials with many other NMDA antagonists.
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