Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.16.2 (PCP)
3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metaphit [an analogue of phencyclidine (PCP) with an acylating isothiocyanate group] induced audiogenic clonic to clonic-tonic seizures in mice exposed to audio stimulation 24 h after metaphit administration. The incidence of seizures was reduced by treatment 30 min before audio stimulation with specific PCP-like compounds [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), and PCP itself], competitive N-methyl-D-aspartate antagonists 2-amino-5-phosphonopentanoic acid (AP-5 and NPC-12626), antiepileptic drugs [phenobarbital (PB), phenytoin (PHT)], and gamma-aminobutyric acid (GABA) agonists (muscimol and diazepam). In contrast, when given in conjunction with metaphit, most of these drugs were ineffective in protecting animals from audiogenic seizures 24 h later. Only compounds with long half-lives (t1/2) such as MK-801, PB, and PHT had a protective effect. High-performance liquid chromatography (HPLC) determination of [3H]MK-801 showed its long-term presence in the brain after intraperitoneal (i.p.) administration of [3H]MK-801. Audiogenic seizures observed 24 h after metaphit administration were potentiated by administration of the GABA antagonist picrotoxin 15 min before audio stimulation, and picrotoxin-induced spontaneous seizures were enhanced by pretreatment (24 h earlier) with a dose of metaphit that in itself did not produce spontaneous seizures at the time of the picrotoxin test. Similar observations were made with N-methyl D-aspartic acid (NMDA) instead of picrotoxin. Thus, an interplay exists between excitatory glutaminergic and inhibitory GABAergic circuitries in the metaphit seizure model.
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PMID:Metaphit-induced audiogenic seizures in mice: I. Pharmacologic characterization. 838 6

The effects of phencyclidine (PCP), an NMDA antagonist, was assessed on a complex task that has been shown to be dependent on hippocampal function. This task required memory for the temporal order of spatial locations. Rats were given IP injections of saline or PCP (3-4 mg/kg) on a double alternation schedule. With PCP injections rats were severely impaired relative to saline injections. Furthermore, PCP was shown to have no effects on the ability of rats to discriminate three-dimensional objects (a task that is not dependent on hippocampal function). The present data, in conjunction with previous results, suggest that the involvement of NMDA receptors in the hippocampus might be a function of the complexity of the task.
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PMID:Phencyclidine impairs temporal order memory for spatial locations in rats. 854 88

The effects of phencyclidine (PCP; a noncompetitive NMDA antagonist) were assessed in rhesus monkeys using performance in an operant test battery (OTB) consisting of five food-reinforced tasks thought to engender responses dependent upon aspects of time estimation, short-term memory, motivation, learning, and color and position discrimination. End-points included percent task completed (PTC), response rate or latency, and response accuracy. Testing occurred 15 min after IV injections of PCP (0.00, 0.003, 0.01, 0.03, 0.1, 0.13, 0.18, and 0.3 mg/kg). PCP disrupted performance of all tasks at 0.30 mg/kg. PTC was significantly decreased in the time estimation, motivation, and learning tasks at doses > or = 0.13 mg/kg. PTC for the short-term memory and color and position discrimination tasks was significantly decreased at 0.18 mg/kg and above. Response rate was significantly decreased at 0.13 mg/kg and above in the motivation and learning tasks and at 0.18 mg/kg and above in the time estimation, short-term memory, and color and position discrimination tasks. Response accuracy was significantly decreased in the time estimation, short-term memory, and learning tasks at doses > or = 0.13 mg/kg, while accuracy in the color and position discrimination task was decreased only at 0.30 mg/kg. PCP's effects on OTB performance were generally nonspecific, in that the time estimation, short-term memory, learning, and motivation tasks were all equally sensitive, with the color and position discrimination task being the least sensitive. These results are different than those obtained from earlier studies on the effects of MK-801, a more selective noncompetitive NMDA antagonist.
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PMID:Acute behavioral effects of phencyclidine on rhesus monkey performance in an operant test battery. 858 21

We have previously shown that a single dose of PCP produces a dose-related increase in NMDA-sensitive 3H-glutamate binding in CA1 of hippocampus 24 hours later, and some regional changes in kainate binding. Here we report that dizocilpine (MK 801) (0.1 mg/kg and 1 mg/kg), a selective agonist at the PCP receptor and a noncompetitive antagonist of NMDA, produces a similar increase in NMDA-sensitive glutamate and kainate receptor binding in hippocampus 24 hours after a dose. These observations support the conclusion that blockade of glutamate-mediated transmission at the NMDA receptor selectively increases NMDA-sensitive glutamate receptor binding in CA1 of hippocampus and kainate binding in CA3 and dentate gyrus at putatively delayed time points. Several additional areas outside of hippocampus also showed receptor changes at 24 hours after MK801.
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PMID:MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain. 869 41

The present study assessed the ability of nitric oxide synthase (NOS) inhibitors to produce PCP-like behavioral effects in pigeons. Food-restricted pigeons were trained to discriminate between PCP (1.0 mg/kg, i.m.) from saline in a two-key operant procedure. NOS inhibitors 7-nitroindazole (7-NI) and N omega-nitro-L-arginine methyl ester (L-NAME) produced PCP-like discriminative stimulus effects. 7-NI (17.8 mg/kg, i.m.) completely generalized to PCP. L-NAME (320-1000 mg/kg) produced partial generalization to PCP. D-NAME, the enantiomer of L-NAME, did not produce PCP-appropriate behavior. L-NAME was approximately 200-times more potent i.c.v., but did not fully generalize to PCP. Both NOS inhibitors were effective in producing catalepsy, which is an effect commonly produced by competitive and uncompetitive NMDA antagonists. 7-NI (32 mg/kg) produced catalepsy in all subjects, whereas L-NAME (3200 mg/kg) produced catalepsy in 50% of the subjects, D-NAME did not produce catalepsy. Pretreatment with L-arginine (32-3200 mg/kg) prevented the PCP-like discriminative stimulus and cataleptic effects of 7-NI (17.8-32 mg/kg), demonstrating that 7-NI produced PCP-like effects through blockade of NO synthesis. The current studies reveal that NOS inhibitors induced two behavioral actions, discriminative stimulus effects and catalepsy, that are very selective for NMDA antagonists in pigeons.
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PMID:Nitric oxide synthase inhibitors produce phencyclidine-like behavioral effects in pigeons. 873 19

NMDA channel blockers are potentially advantageous therapeutic agents for the treatment of ischemia and head trauma, which greatly elevate extracellular glutamate, because they should most effectively inhibit high levels of receptor activation. A novel high affinity TCP site ligand, WIN 63480, does not produce MK-801- or PCP-like behavioral activation at anti-ischemic doses. While WIN 63480, MK-801 and PCP were all observed to be effective blockers of open NMDA channels, WIN 63480 had much less access to closed NMDA channels. This difference may be due to the fact that WIN 63480 is hydrophilic (logD = -4.1) while MK-801 and PCP are lipophilic (logD = +1.8). In vivo, closed channel access may result in a non-competitive profile of antagonism for MK-801 and PCP compared to a more uncompetitive profile for WIN 63480. Release of glutamate, and depolarization, are likely to produce a high level of NMDA receptor activation in ischemic areas compared to normal tissue. Consequently, at anti-ischemic doses, WIN 63480 may produce less inhibition of physiological NMDA-mediated processes in neural systems involved in behavioral regulation than MK-801 or PCP, leading to an improved side effect profile.
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PMID:WIN 63480, a hydrophilic TCP-site ligand, has reduced agonist-independent NMDA ion channel access compared to MK-801 and phencyclidine. 878 57

We have estimated the affinity of the antiparkinsonian drug budipine to the PCP binding site of the NMDA receptor and to sigma 1 binding sites in membranes from postmortem human brain frontal cortex. The affinity of budipine to both binding sites is in a concentration range that may be reached under therapeutic conditions (Ki-values of about 12 and 2 microM at the PCP and sigma 1 binding site, respectively). Interactions with NMDA receptors as well as sigma 1 binding sites may contribute to the antiparkinsonian effects of budipine.
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PMID:The antiparkinsonian drug budipine binds to NMDA and sigma receptors in postmortem human brain tissue. 882 Oct 48

Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.
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PMID:Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. 884 37

Phencyclidine (PCP) produces a psychotic reaction in humans which closely resembles an acute episode of schizophrenia and has therefore been given an increasing amount of attention as a model for schizophrenia. The present article reviews the behavioral and neurochemical effects of PCP in both humans and animals. Where possible, comparisons are made between the effects of PCP and amphetamine. The merits of the dopamine versus NMDA/PCP receptor mediated expression of PCP-induced psychosis are discussed, as well as the importance of selecting behavioral models which are best suited to model the expression of psychosis, rather than the motor effects of psychotomimetics.
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PMID:The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis. 885 14

The physiological model for glutamate receptor mediated excitotoxicity entails elevation of intraneuronal calcium levels. Excessive activation of the NMDA receptor leads to excitotoxicity by prolonged calcium influx via its calcium channel. The purpose of this research was to examine the mechanism of non-NMDA glutamate receptor mediated excitotoxicity. Mammalian AMPA receptors do not show significant calcium conductance. However, some kainate receptors show significant calcium conductance. The hypothesis of this research states that non-NMDA glutamate agonists (quisqualate (5 microliters of 2 mg/ml i.c.v.), AMPA (4 microliters of 1 mg/ml i.c.v.), and kainate (15 mg/kg i.p.)) produce significant heat shock gene, hsp70, induction via glutamate release with subsequent opening of the NMDA receptor calcium channel. PCP (phencyclidine) and ketamine are noncompetitive blockers of the NMDA calcium channel. They act to prevent significant NMDA receptor excitotoxicity. PCP (20 mg/kg i.p.) and ketamine (60 mg/kg i.p.) both diminished quisqualate and AMPA hsp70 induction in the CA1, CA2, CA3 areas of the hippocampus, in the polymorph area of the dentate gyrus, and in the parietal neocortex. PCP significantly (P < 0.05) diminished kainate hsp70 induction only in the CA1 area and the neocortex. Ketamine failed to reduce kainate hsp70 induction. AMPA receptors appear to result in excitotoxic damage via glutamate release. Glutamate opens NMDA receptor calcium channels which increases intraneuronal calcium levels. Kainate receptors probably mediate excitotoxicity via direct calcium conductance with glutamate release being important in the CA1 area and neocortex.
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PMID:PCP and ketamine inhibit non-NMDA glutamate receptor mediated hsp70 induction. 886 85


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