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)

It is no longer tenable to attribute all the antipsychotic action of antipsychotic drugs to dopamine (DA) D2 receptor blockade and subsequent development of depolarization inactivation of the mesolimbic or mesocortical DA neurons. The chief evidence for this position is that clozapine (CLOZ) does not differ from typical antipsychotic drugs in these regards but is more effective than typical neuroleptic drugs. The mechanism of action of atypical antipsychotic drugs related to CLOZ may involve reduction of dopaminergic activity in the mesolimbic system by a variety of mechanisms, including D1 and D2 receptor blockade. Relatively higher affinity for the serotonin (5HT)2 receptor than for the D2 receptor may also be important to the action of CLOZ-like compounds. Enhanced DA release in the mesocortical system may be relevant to the effectiveness of these agents in treating negative symptoms. Several other classes of new agents alter the dopaminergic system by means of alternative mechanisms. Partial DA agonists may modulate DA neurotransmission more adequately than pure antagonists by producing a mix of direct agonist and antagonistic effects. DA autoreceptor agonists and 5HT3 antagonists appear to act by diminishing the release of DA from some, but not all, DA neurons. Substituted benzamides are "pure" D2 antagonists with some in vivo selectivity for limbic D2 over striatal D2 receptors. Highly selective D1 antagonists have been proposed to produce equivalent antipsychotic activity and fewer extrapyramidal symptoms than D2 antagonists. Antagonists of the recently identified D3 receptors are being sought. Excessive stimulation of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, leading to neurotoxicity or diminished activation of this receptor, is the target of novel approaches to treating schizophrenia. Phencyclidine (PCP) antagonists that would activate the NMDA receptor and sigma receptor antagonists are of interest as antipsychotic agents. Therapeutic strategies for treating schizophrenia, schizophrenia-related disorders, and other psychoses will likely be genuinely diverse in the next decade.
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PMID:The mechanism of action of novel antipsychotic drugs. 167 53

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.
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PMID:NMDA antagonist neurotoxicity: mechanism and prevention. 183 99

The release of free [3H]arachidonic acid and its metabolites (AAM) from mouse embryo cortical neurones cultured in serum-free medium stimulated by beta-endorphin C-terminal dipeptide (glycl-L-glutamine, Gly-Gln) was investigated. Gly-Gln but not the related dipeptide, glycyl-glutamic acid, caused a 2-fold elevation of AAM release which was blocked in the absence of extracellular calcium, in the presence of 5 mM magnesium and by the phospholipase A2 (PLA2) inhibitor, mepacrine. Other proopiomelanocortin (POMC) peptides did not elicit AAM release. The response to Gly-Gln was unaffected by D-amino-2-phospho-5-valeric acid (AP5) and 7-chlorokynurenic acid (7-ClKY), antagonists respectively at the ligand and allosteric glycine binding sites of the NMDA glutamate receptor subtype. However, it was inhibited in a dose-dependent manner by antagonists at the phencyclidine (PCP) and sigma sites. The results suggest that Gly-Gln causes AAM release by activating PLA2 through the mediation of a PCP/sigma-like receptor.
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PMID:Beta-endorphin C-terminal peptide evokes arachidonic acid release from cortical neurones. 190 34

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

In rats receiving N-methyl-D-aspartate (NMDA) intraventricularly or intracisternally the cerebellar cyclic guanosine monophosphate (cGMP) content increases in a dose-related manner. This response was used to study phencyclidine (PCP) and glycine interactions with the glutamate receptor subtype stimulated by NMDA. The increase of cGMP elicited by NMDA was inhibited by PCP and potentiated by glycine. Moreover, 2-amino-5-phosphonovalerate (APV) abolished the NMDA response. Since the increase in cerebellar cGMP induced by kainate, a synthetic agonist of another glutamate receptor subtype, was not modified by APV, the specificity of its action on NMDA response was confirmed. The increase of cerebellar cGMP content elicited by glycine was inhibited by PCP and APV but not by strychnine. Binding studies failed to demonstrate an apparent competitive interaction between PCP, glycine and NMDA. This suggests that the observed interaction is not of the isosteric type. The present results provide evidence that glycine, in vivo, acting at strychnine-insensitive recognition sites modulates allosterically in a positive manner the function of NMDA-sensitive glutamate receptors.
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PMID:Modulation of glutamate receptors by phencyclidine and glycine in the rat cerebellum: cGMP increase in vivo. 253 9

Phencyclidine (PCP) was tested on the metathoracic tibialis muscles of Locusta migratoria. In physiological solution, the peak amplitude of the excitatory postsynaptic currents (EPSCs) evoked by nerve stimulation was linearly related to membrane potential between -50 and -150 mV. The decay time constant of the EPSC (tau EPSC) was exponentially dependent on voltage and decreased with hyperpolarization. The membrane potential change required to produce an e-fold change in tau EPSC was 315 mV. PCP (5-40 microM) produced a concentration-dependent depression of both EPSC peak amplitude and tau EPSC. A slight nonlinearity in the current-voltage relationship could be discerned at high concentrations of PCP. The shortening of the decay time constant of EPSC (tau EPSC) occurred without significant change in the voltage sensitivity observed under control conditions. Under all experimental conditions, the decay of the EPSCs remained a single exponential of time. Fluctuation analysis indicated that 5 microM PCP shortens the lifetime of the glutamate-activated channels by 25.7 +/- 3%. PCP (10-80 microM) did not induced desensitization of the glutamate receptors. These results suggest that PCP interacts with the open conformation of ion channels activated by the glutamate receptor.
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PMID:Phencyclidine (PCP) blocks glutamate-activated postsynaptic currents. 286 72

Considerable research has identified a variety of acute PCP-induced biochemical changes in brain; but, little study has been devoted to characterizing delayed PCP-induced actions. These could potentially be associated with the prolonged psychotomimetic effects of the drug in humans. Here we studied delayed PCP-induced alterations in glutamate receptor subtype binding across a range of PCP doses, based on our previous findings of delayed regional cerebral metabolism changes with PCP. We report that 24 h after a single dose, PCP increases N-methyl-D-aspartate (NMDA)-sensitive [3H]glutamate binding in hippocampus (CA1) in an apparent dose-sensitive manner; no other dose-sensitive regional changes in NMDA binding sites were apparent in a sampling of 19 brain regions. [3H]kainate binding sites were increased in CA3 and dentate gyrus, but only at the high drug dose. Moreover, PCP appeared to have a general delayed effect in upregulating NMDA receptor binding in limbic-associated brain areas at its middle dose, and in upregulating [3H]kainate binding in neocortical and limbic areas at its high dose. No PCP effects were noted on AMPA receptor binding. These delayed actions of PCP may be informative about the mechanism of PCP psychosis.
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PMID:An increase in NMDA-sensitive [3H]glutamate and [3H]kainate binding in hippocampus 24 hours after PCP. 797 Jan 71

MK-801, a high-affinity phencyclidine (PCP) analogue, is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptor that elicits hyperactivity, stereotypic behaviors, and "popping," an explosive episodic jumping behavior, in mice. The schizophreniform psychosis precipitated by PCP in humans has stimulated interest in studying MK-801-elicited mouse behaviors for their potential development as animal models of idiopathic psychosis. We describe a computerized method for measuring popping and hyperactivity elicited by MK-801 in mice, based on vertical displacements of a platform. This computerized procedure allows for the automatic measurement of discrete "pops" per individual episode of popping behavior, the force of each one of the explosive jumps, and the duration of discrete episodes of popping; these latter measures could not be easily ascertained by visual inspection alone. Moreover, the computerized measurements facilitate quantitative evaluation of the effects of pharmacological manipulations on MK-801-elicited popping. For example, the antipsychotic haloperidol was shown to reduce significantly both MK-801-induced popping and hyperactivity. Ideally, MK-801-elicited mouse popping and hyperactivity will serve as a useful preclinical screening paradigm for potential antipsychotic medications. Additionally, it is hoped that the use of this automated system will contribute to a greater understanding of the mechanisms of MK-801-induced popping and hyperactivity.
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PMID:Computerized measurement of MK-801-elicited popping and hyperactivity in mice. 866 59

Glutamate receptor antagonists with selective action at the N-methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neuropsychiatric disorders. Although NMDA receptor antagonists of the phencyclidine (PCP) type are precluded from clinical use because of their psychotomimetic properties, amantadine and memantine have been administered to human patients with idiopathic Parkinson's disease and spasticity for many years without serious adverse effects. The mechanisms underlying these differences in psychotogenicity of different NMDA receptor antagonist are currently being discussed. Different affinity to the PCP binding site of the NMDA receptor, region-specific pharmacology, as well as different binding profiles to neurotransmitter receptors other than the NMDA type glutamate receptor, most likely play a role in determining whether an NMDA receptor antagonist drug will be tolerated clinically or not.
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PMID:[New therapeutic possibilities with low-affinity NMDA receptor antagonists]. 867 93

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


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