Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency of dizocilpine > TCP > (-)-MK-801 > SKF 10,047 > dextrorphan > PCP. There was a positive correlation between the potencies of the compounds that substituted for dizocilpine and their previously reported affinities for the [3H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABAA receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17742, (+/-)CPP and LY 233536 dose-dependently substituted for dizocilpine. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive NMDA blockers.
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PMID:Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice. 933 79

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.
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PMID:Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys. 983 79

The effects of the competitive NMDA antagonists, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) and 3-(2-carboxypiperazin-4-yl) propyl-l-phosphonic acid (CPP), were compared to those of the noncompetitive NMDA antagonists, phencyclidine (PCP) and (+)-5-methyl-10, 11-dihydro-5H-dibenzo (a,d) cyclohepten-5, 10-imine maleate (MK-801), in male Sprague-Dawley rats trained to discriminate 5 mg/kg (+)-N-allyl-normetazocine (NANM) from saline under a standard two-lever fixed-ratio 32 schedule of food reinforcement. (+) - NANM, PCP and MK-801 dose-dependently substituted for the training dose of (+) - NANM in all rats tested. Conversely, NPC 12626 and CPP produced no more than an average of 73% (+) - NANM-lever responding at doses that also reduced response rates by more than 50% of corresponding control response rates. Methohexital also produced an average of 50% (+) - NANM-lever responding at doses that reduced response rates. In addition to supporting a role for the PCP receptor in transducing the discriminative stimulus effects of (+) - NANM, these results lend further evidence for differences in the behavioral effects of competitive and noncompetitive NMDA antagonists.
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PMID:(+)-N-Allylnormetazocine (NANM)-like discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists. 1117 30

The acute effects of ethanol (EtOH) on fixed-ratio performance were studied in separate lines of mice selectively bred for differences in severity of handling-induced convulsions following withdrawal from EtOH. Because modulation of N methyl-D-aspartate (NMDA) receptors has been implicated in production of the acute and withdrawal-induced effects of EtOH, we also tested NMDA and three NMDA antagonists. Withdrawal seizure-resistant (WSR2) mice were more sensitive to the response rate-decreasing effects of EtOH than were withdrawal seizure-prone (WSP2) mice. Similar to EtOH, NPC 12626 (a competitive NMDA antagonist) and phencyclidine (a non-competitive NMDA antagonist) decreased responding in WSR2 mice at doses that did not affect responding in WSP2 mice. Although a second non-competitive NMDA antagonist, dizocilpine, produced line differences in the same direction as did PCP, these differences were not statistically significant. In contrast, NMDA produced nearly equipotent dose-dependent response rate decreases in both lines. Combined with the results of previous in vitro studies which showed that the number of NMDA receptors in the hippocampi of WSR2 and WSP2 mice differ, the results of the present study suggest that the interaction of EtOH with NMDA receptors may contribute to differences in the acute effects of ethanol on schedule-controlled behavior in WSP2 and WSR2 mice.
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PMID:Effects of ethanol and NMDA antagonists on operant behavior in ethanol withdrawal seizure-prone and-resistant mice. 1122 77

Both enhancement of GABAergic neurotransmission and antagonism of glutamatergic neurotransmission involving the NMDA receptor have been implicated in the acute effects of ethanol. In this study, rats were trained to discriminate 1000mg/kg ethanol from saline. This dose of ethanol was consistently discriminated from saline but had no effects on overall rates of responding. Substitution tests were conducted with a number of GABA agonists and NMDA antagonists. Both midazolam and pentobarbital exhibited substantial substitution for ethanol at doses that moderately decreased response rates. However, muscimol and baclofen completely failed to substitute for ethanol, as did a combination of a fixed dose of muscimol with increasing doses of baclofen. The non-competitive NMDA antagonists PCP, dizocilpine and ketamine substituted fully for ethanol, but only at doses that also substantially suppressed rates of responding. The competitive NMDA antagonists, CPPene and NPC 17742, partially substituted for ethanol. The levels of substitution for ethanol among the indirect GABA agonists and the non-competitive NMDA antagonists indicate that the discriminative stimulus effects of ethanol, at least at a 1000mg/kg dose, may involve both GABAergic and glutamatergic systems.
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PMID:Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. 1122 96

Antagonists at the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor are purported to have detrimental effects on cognitive processes. In order to examine the site selectivity of these effects, phencycline (PCP), dizocilpine, and memantine (PCP-site antagonists), SDZEAA 494 and NPC17742 (competitive NMDA antagonists), ACEA 1021 (glycine-site antagonist), and eliprodil (NR2B-selective polyamine-site selective antagonist) were tested in rats performing a delayed nonmatch-to-sample task. Dizocilpine, PCP and memantine significantly decreased accuracy and discriminability, particularly during brief delay trials. In contrast, the competitive NMDA antagonists, SDZ EAA 494 and NPC 17742, did not affect accuracy or discriminability at any delay. Similarly, ACEA 1021, and eliprodil did not alter behavioral indices in a manner suggesting compromise in information processing at any delay even at doses that decreased the total number of trials completed. These data support previous findings that the effects of NMDA antagonists on accuracy are site-selective, with PCP-site antagonists producing the greatest disruption. Further, while not conclusive, the results are consistent with the hypothesis that NMDA receptor-mediated neurotransmission may be important at early stages of information processing, although further research is necessary to confirm these latter observations.
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PMID:NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats. 1174 96


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