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)

Huntington's disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.
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PMID:Huntington's disease as a model for mood disorders. Clues from neuropathology and neurochemistry. 214 28

Evidence from electropharmacological experimentation favors the hypothesis that the PCP site is intimately associated with the channel domain of the NMDA receptor. But it is too early to state that this site lies deep within the NMDA channel pore. Determining the molecular details of the PCP site will require a complete and detailed kinetic analysis of NMDA single channel behavior. Furthermore, it is likely that hydrophobic receptor site(s) are responsible for some aspects of the blockade by at least some members of the dissociative anaesthetic family.
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PMID:The PCP site of the NMDA receptor complex. 215 Jan 54

Several lines of evidence suggest a tight functional coupling between N-methyl-D-aspartate (NMDA) and phencyclidine (PCP) receptors. The effects of PCP receptor agonists (PCP, dexoxadrol, ketamine and MK-801) and NMDA receptor antagonists, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) and 3-(2-carboxypiperizin-4-yl)-propyl-1-phosphonic acid (CPP), have been examined on the metabolism of dopamine in the mesocortex, with a view of studying the coupling between these two receptor systems. Phencyclidine receptor agonists selectively increased the metabolism of dopamine in the mesocortex without affecting the metabolism of dopamine in the striatum. N-Methyl-D-aspartate and the competitive antagonists of NMDA receptors did not effect the metabolism of dopamine, neither did the sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) and rimcazole. Rimcazole also did not affect the increases in the metabolism of dopamine in the mesocortex, seen after MK-801. These data indicate that dopaminergic neurons in the mesocortex are positively modulated by PCP receptors but tentatively suggest that those recognition sites for PCP are not coupled to NMDA receptors.
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PMID:Selective activation of dopaminergic pathways in the mesocortex by compounds that act at the phencyclidine (PCP) binding site: tentative evidence for PCP recognition sites not coupled to N-methyl-D-aspartate (NMDA) receptors. 215

Recently, it was found in studies in vitro and in vivo that phencyclidine hydrochloride (PCP, 'angel dust') can induce cerebral arterial and arteriolar spasms, in psychotomimetic concentrations, by acting on specific PCP receptors, which is followed by rupture of cerebral and postcapillary venules. We wondered whether a chemical substance which has the ability to block Ca2+ channels, neurotransmitter release, intracellular Ca2+ release and the NMDA-glutamate receptor channel, viz., Mg2+, might block the PCP receptor which subserves cerebral contractile events and thereby prevent rupture of microvessels. In vivo experiments carried out on cerebral microvessels in a rat pial brain preparation revealed that different dose regimens of Mg aspartate HCl administered intravenously attenuated cerebrovasospasms induced by PCP and shifted PCP concentration-effect curves (ED50) rightward to higher concentrations. These data suggest that Mg2+ may alter the binding of PCP for its vascular receptors. Since Mg2+ prevented rupture of the cerebral microvessels, it may prove useful, clinically, in prevention and treatment of PCP-intoxicated victims.
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PMID:Mg2+ protects against PCP-induced cerebrovasospasms and vascular damage in rat brain. 215 88

A rapid kindling procedure was used to distinguish between the anticonvulsant activity of drugs and their ability to retard the kindling process. MK-801 is a specific ligand at the phencyclidine (PCP) recognition site, and acts as a noncompetitive antagonist of NMDA-type glutamate/aspartate receptors. Intraperitoneal injections of MK-801 (0.5-4.0 mg/kg IP) significantly reduced the cumulated effect of 12 2-hr kindling stimulations, as determined from behavioral measures of seizure activity in immediately ensuing 24-hr drug-free kindling sessions; however, the corresponding electrographic effects did not reach significance. MK-801 also showed significant anticonvulsant activity when injected in fully kindled rats. Higher doses tested were accompanied by locomotor and postural effects. The anticonvulsant benzodiazepine, clonazepam, formulated with a proprietary diluent (as Rivotril, Roche), injected in anticonvulsant doses during the first 12 kindling sessions (0.64 mg/kg IP, repeated after 9 hr) did not significantly affect the course of subsequent sessions of drug-free kindling. Systemic injections of kynurenic acid (300-600 mg/kg IP 4 hours), a nonspecific antagonist of glutamate receptors in vitro, were without significant anticonvulsant or antikindling activity. Activity of NMDA-sensitive glutamate/aspartate receptors associated with the PCP recognition site may induce lasting facilitation of neural transmission; this facilitation may be responsible for the remote propagation and progressive enhancement of seizure activity kindled in the amygdala. The facilitatory process appears to be antagonised by MK-801.
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PMID:The effect of the NMDA receptor antagonist, MK-801, on the course and outcome of kindling. 216 Nov 8

The effects of dizocilipine (MK-801), (+/-)-5-methyl-10,11-dihydro-5Hdibenzo-[a,d]-cyclohepten-5, 10-imine maleate, after IP injection into freely behaving rats, have been compared with the action of ketamine-chloride and phencyclidine (PCP). MK-801 produced strongly dose-dependent effects which could be followed quantitatively over a time of 4 h. During this time spectral analysis of the field potentials continuously recorded from frontal cortex, hippocampus, striatum, and reticular formation revealed a particular pattern of changes which was very stable over time, and after low doses of 0.05 and 0.1 mg/kg, matched that produced by phencyclidine (2 and 4 mg/kg) or ketamine chloride (10 and 20 mg/kg). With higher doses of MK-801 a continuous change from power decreases to power increases was observed. These increases were accompanied by strong behavioral effects in terms of impaired locomotor control. All three non-competitive NMDA antagonists showed a high degree of similarity with respect to the changes of the frequency content of the field potentials over time. The same pattern of electrical changes could be observed after the application of L-dopa (50 mg/kg) or amphetamine (0.2 mg/kg). This can be interpreted in the sense that the same population of cells within the recording area which is under dopaminergic control is at the same time under glutamate control. This leads to the hypothesis that it might be possible to bypass the missing dopaminergic control during parkinsonism by noncompetitive NMDA-receptor blocking drugs.
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PMID:Dizocilpine (MK-801), ketamine and phencyclidine: low doses affect brain field potentials in the freely moving rat in the same way as activation of dopaminergic transmission. 216 37

Ketamine has been employed as an anesthetic for 25 years. It is the only PCP-like dissociative anesthetic in clinical use. Favourable experience with ketamine in combat situations and at accidents, together with its ability to block the effect of the excitatory neurotransmitter glutamate on NMDA-receptor mediated neurotransmission, has attracted greater attention to this drug in recent years. The indications for and the use of ketamine as an anesthetic is described, and its various side-effects discussed. Combination with benzodiazepines greatly reduces these side-effects. Several pharmacological mechanisms may contribute to the effects of ketamine, in particular when large (anesthetic) doses are given. Recent investigations indicate that the analgesic and anesthetic effects as well as the "dissociative" phenomena seen after analgesic doses are due to PCP receptor mediated inhibition of excitatory amino acid transmission at NMDA synapses. The excitatory effect observed at higher doses, however, may be mediated by the haloperidol sensitive sigma-receptor. The enantiomers of ketamine (R- and S-ketamine) differ in pharmacological profile and may enable improvement of ketamine as a drug.
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PMID:[Ketamine: clinically useful--pharmacologically interesting]. 216 88

Phencyclidine (PCP) binds with high affinity to the ion channel associated with the NMDA receptor. The binding of the PCP receptor-specific ligand TCP is greatly reduced at temperatures between 2 degrees C and 6 degrees C, at which the plasma membrane is in a rigid state. However, membrane rigidity alone does not appear to cause the reduced TCP binding, since the membrane fluidizing agent A2C did not increase TCP binding at 4 degrees C; instead, it decreased binding at 21 degrees C. This inhibitory effect of A2C on TCP binding was dose dependent and was highly correlated with A2C-induced increases in membrane fluidity. The IC50 of A2C inhibition was 8.9 mM, with a pseudo-Hill coefficient of -0.24. Scatchard analysis demonstrated that this effect was the result of an increase in the apparent KD of [3H]TCP for the PCP receptor, with no effect on the Bmax. These results suggest that the function of the NMDA-PCP receptor complex is impaired by increases in membrane fluidity. These findings may be pharmacologically relevant in understanding the mechanism of action of such agents as general anesthetics and ethanol, which cause increases in plasma membrane fluidity.
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PMID:Effects of membrane fluidity on [3H]TCP binding to PCP receptors. 217 11

The effects of non-NMDA receptor agonists were tested on endogenous GABA and [3H]GABA release from highly purified striatal neurons differentiated in primary culture. Kainate (KA), glutamate (Glu) and quisqualate (QA) stimulated [3H]GABA release with EC50S = 85 +/- 20 (n = 6), 6.21 +/- 1.42 (n = 3) and 0.135 +/- 0.035 (n = 3) microM, respectively. KA was the most potent (in term of efficacy) agonist (maximal response at 10 mM: 935 +/- 51% (n = 6) increase over basal release) followed by Glu (at 100 microM: 404 +/- 34% (n = 5) increase) and QA (at 10 microM: 91 +/- 6% (n = 6) increase). Phencyclidine (PCP), which was without effect on QA- and KA-evoked GABA release, inhibited the Glu response by about 50%. QA totally inhibited KA (50 microM)-evoked GABA release with an IC50 = 0.39 +/- 0.11 (n = 4) in a competitive manner (Ki = 0.39 +/- 0.07 microM (n = 3]. Competitive inhibition of the KA response was also observed with the other agonists of the quisqualate receptor, Glu and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), suggesting that Glu, QA and AMPA act as partial agonists at the KA receptor. gamma-D-Glutamylaminomethylsulfonic acid (GAMS) also inhibited (IC50 = 2.1 mM) the KA response competitively. However the inhibition by GAMS and QA was not additive. The response to QA was rapidly inactivated (no response after 3 min stimulation) in contrast to the KA-evoked GABA release which remained maximal for at least 3 min. When neurons were first exposed to concanavalin A (con A), a lectin known to inhibit Glu receptor desensitisation on insect muscles, the QA response remained maximal for at least 6 min. Con A greatly enhanced the maximal responses to QA and AMPA and decreased their apparent affinities. The KA-evoked GABA release (but not the veratridine and NMDA effects) was also augmented (no change in the EC50 value) by con A. It is proposed that QA, AMPA and KA act at the same receptor-channel complex (termed G2 receptor) which is desensitised more rapidly when stimulated by QA or AMPA than when stimulated by KA.
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PMID:Complex interaction between quisqualate and kainate receptors as revealed by measurement of GABA release from striatal neurons in primary culture. 254 Oct 1

1. As reported for many other PCP receptor actions, the pharmacological profile of PCP receptor agonists and NMDA receptor antagonists were similar with regard to their effects on cerebellar cGMP levels in vivo. 2. PCP receptor agonists act to increase mesocortical dopamine (DA) metabolism and release. 3. This receptor action is stereospecific and is both dose- and time-dependent. 4. The actions of PCP on DA metabolism appear to involve PCP receptors both in the ventral tegmental area (VTA) and the cortical nerve terminal regions. 5. In contrast to many other systems which have been studied, competitive NMDA antagonists do not act in a manner similar to PCP agonists, with regard to mesocortical DA metabolism. 6. Sigma receptor ligands and NMDA agonists also do not alter mesocortical DA metabolism. 7. These data suggest that the PCP receptor population which modulates mesocortical dopaminergic neurons is not coupled to NMDA receptors.
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PMID:NMDA-coupled and uncoupled forms of the PCP receptor: preliminary in vivo evidence for PCP receptor subtypes. 254 81


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