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)

Amphetamine induced psychosis has for the past 30 years provided a useful model for the study of schizophrenia. The amphetamine model, however, has been shown to have a number of shortcomings including an inability to model the deficit symptoms of schizophrenia. PCP (phencyclidine) has been shown to be capable of inducing a schizophreniform psychosis consisting of both productive and defict symptomatology. PCP induced psychosis, therefore, may provide a useful model of schizophrenia. This paper reviews the literature concerning the PCP model of schizophrenia and provides some independent confirmation of the ability of PCP to modulate mesocortical dopaminergic activity. Since PCP appears to mediate its CNS effects via a subclass of glutamate receptors, a possible glutamate theory of schizophrenia is proposed.
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PMID:Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. 282 Aug 54

The ability of phencyclidine (PCP) to model schizophreniform psychosis is believed to be related to its ability to produce both hypoglutamatergia and hyperdopaminergia. As such, identification of PCP-stimulated behaviors may be important for the development of animal models of schizophrenia. In this study, MK-801 [(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cycloheptane-5,10-imine maleate], a high-affinity PCP analogue, was administered to mice in order to stimulate "PCP behaviors." These PCP behaviors were compared with behaviors stimulated by apomorphine, a dopamine agonist. Stereotyped behavior was assessed by both visual observations and automated measurements. Visual observations showed highly intense gnawing and sniffing in apomorphine-treated mice and the absence of gnawing in MK-801-treated mice. Automated stereotypic measures showed that, compared with vehicle-treated controls, there were frequent dissociations between MK-801 and apomorphine. Conceivably, a compound that attenuates PCP-stimulated behaviors while sparing apomorphine-stimulated behaviors would possess both antipsychotic efficacy and be devoid of undesirable side effects associated with dopamine blockade.
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PMID:Differentiation between MK-801- and apomorphine-induced stereotyped behaviors in mice. 850 39

MK-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor complex that binds with high-affinity to the phencyclidine (PCP) binding site, stimulated an outbred strain of NIH Swiss mice to display discrete episodes of explosive jumping behavior, designated as "popping." The episodes of this behavior were characterized with respect to their dose dependency, latency, and duration. The number of mice displaying this behavior increased with increasing doses of MK-801. The intensity of the popping behavior was sensitive to dose-dependent inhibition by haloperidol, a conventional antipsychotic medication, and clozapine, an atypical antipsychotic medication. In view of PCP's ability to precipitate a schizophreniform psychosis in humans, the behavior may serve as a useful preclinical paradigm for the screening of potentially novel antipsychotic medications.
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PMID:Measurement of an explosive behavior in the mouse, induced by MK-801, a PCP analogue. 850 42

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

To clarify the molecular mechanism of phencyclidine (PCP)-induced schizophreniform psychosis in humans and of behavioral abnormalities in experimental animals, we used differential screening of a cDNA library from the cerebral cortex of rats treated with PCP. We identified a PCP-induced cDNA clone as the gene encoding glutamate dehydrogenase (GDH), an enzyme central to glutamate metabolism. GDH mRNA levels significantly increased as early as 15 min following PCP administration in both the cerebral cortex and the cerebellum. This effect was observed even in the presence of a protein synthesis inhibitor, cycloheximide. In contrast to a transient increase in c-fos expression, the elevation of GDH mRNA levels lasted up to 8 days after a single PCP injection. These results suggest that GDH mRNA induction may be involved in the pathology of PCP-induced psychosis, and that GDH may be one of the candidate genes that are vulnerable in subjects with schizophrenia.
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PMID:Glutamate dehydrogenase mRNA is immediately induced after phencyclidine treatment in the rat brain. 926 80

Altered neurotransmission mediated by L-glutamate at the level of the N-methyl-D-aspartic acid (NMDA) receptor complex has been implicated in the pathophysiologic mechanisms of several major neuropsychiatric disorders. Moreover, strategies for the pharmacologic manipulation of NMDA-mediated neural transmission have been discussed for the treatment of disorders as diverse as schizophrenia, seizures, stroke, and traumatic brain injury, MK-801, an uncompetitive allosteric antagonist of the NMDA receptor complex, was shown to antagonize electrically precipitated seizures in a dose-dependent manner and elicit popping behavior in mice. Changes in the ability of MK-801 to antagonize electrically precipitated seizures or elicit popping behavior caused by stress or pharmacologic manipulations may reflect alterations in the populations of NMDA-associated channels responsible for these behavioral actions (e.g., the number of them in the open configuration or their size, shape, and charge characteristics). We used these paradigms to study the pharmacologic actions of an allosteric glycinergic intervention (i.e., milacemide), inhibitors of the "nitric oxide cascade" (i.e., 7-nitroindazole and methylene blue), and conventional (i.e., haloperidol) and atypical (i.e., clozapine) antipsychotic medications on NMDA-mediated neurotransmission in the intact mouse. Also, marked differences in the ability of MK-801 to elicit popping behavior in inbred mouse strains suggest that they differ in their populations of NMDA receptor complexes responsible for mediating this behavior. This latter observation could lend itself to the identification of specific genetic loci contributing to this behavior. In view of the ability of phencyclidine (PCP) to precipitate a schizophreniform psychosis and the action it shares with MK-801 on NMDA-mediated neurotransmission, the characterization of these genetic loci in mice may inform the search for human loci responsible for the susceptibility to "PCP-psychosis" and schizophrenia.
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PMID:Behavioral approaches to the functional assessment of NMDA-mediated neural transmission in intact mice. 933 13

The phencyclidine (PCP) model of schizophrenia suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction and its consequences may play an important role in the pathophysiology of this psychiatric disorder. Moreover, the schizophreniform psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, especially negative symptoms and cognitive dysfunction. Because of interest in the PCP model and possible NMDA receptor hypofunction in schizophrenia, animal behaviors elicited by PCP and its analogues have been characterized. These preclinical models may serve to identify candidate compounds that possess therapeutic efficacy in schizophrenia. Ideally, negative symptoms and cognitive dysfunction would also serve as therapeutic targets for these novel medications. In the current study, the ability of topiramate to attenuate the severity of a specific behavior elicited by MK-801 (dizocilpine), a high affinity analogue of PCP was studied in mice. Topiramate was chosen because it addresses two of the predicted pathological consequences of NMDA receptor hypofunction. Specifically, topiramate potentiates GABAergic neurotransmission and antagonizes the excitotoxic actions of glutamate at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) classes of glutamate-gated channels. Topiramate was shown to inhibit MK-801-elicited "popping" behavior in a complex dose-dependent manner.
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PMID:Topiramate antagonizes MK-801 in an animal model of schizophrenia. 1216 15

The ability of phencyclidine (PCP), a noncompetitive antagonist of NMDA receptor-mediated neurotransmission, to precipitate a schizophreniform psychosis in susceptible individuals is consistent with the hypothesized pathologic occurrence of NMDA receptor hypofunction in this disorder. Because the psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, investigators have sought to characterize animal models of NMDA receptor hypofunction. MK-801 (dizocilpine) binds to the same hydrophobic channel domain in the NMDA receptor-associated ionophore as PCP, and has been shown to elicit intense irregular episodes of jumping behavior in mice, termed "popping." MK-801-elicited mouse popping is an animal model of NMDA receptor hypofunction that has been used to screen novel candidate compounds for the treatment of schizophrenia. Recently, a selective abnormality in the transduction of the acetylcholine signal at the level of the alpha 7 nicotinic receptor has been described in schizophrenia. The existence of a nicotinic cholinergic abnormality in schizophrenia has stimulated interest in a potential therapeutic role for positive allosteric modulation of nicotinic receptors. Galantamine is a compound that possesses two interesting properties: inhibition of acetylcholinesterase and positive allosteric modulation of nicotinic neurotransmission. Theoretically, galantamine would be expected to increase the efficiency or likelihood that acetylcholine will promote channel opening and ionic conductance at nicotinic receptors. As expected, in the current investigation statistically significant popping behavior was elicited by MK-801 in mice (T(22) = 2.16, P < 0.05). This MK-801-elicited popping was significantly attenuated by 100 mg/kg of galantamine (T(22) = 2.24, P < 0.05). The data show that nicotinic interventions can influence NMDA receptor-mediated neurotransmission in the intact mouse.
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PMID:Modulation of MK-801-elicited mouse popping behavior by galantamine is complex and dose-dependent. 1294 37

The expression of the alpha7-nicotinic acetylcholine receptor is diminished in selected brain areas of patients with schizophrenia. This diminished expression may account for the pathophysiological deficits of sensory inhibition and smooth pursuit eye movement performance in these patients. Furthermore, the deficits in sensory inhibition and smooth pursuit eye movement performance in schizophrenia appear to be inherited in an autosomal dominant fashion; thus, the "alpha7-nicotinic acetylcholine receptor-deficiency" may be a necessary condition for expression of schizophrenia. This deficit has encouraged speculation about the possible therapeutic benefit of selective alpha7-nicotinic acetylcholine receptor agonist interventions in this disorder. In view of this, we sought to examine the effect of anabasine, a selective alpha7-nicotinic acetylcholine receptor agonist, on popping behavior in mice elicited by MK-801. MK-801, a high affinity analogue of phencyclidine (PCP), is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that binds to the hydrophobic domain of this ligand-gated channel. PCP is known to precipitate a schizophreniform psychosis in susceptible individuals, causing productive (e.g. hallucinations) deficit (e.g. affective blunting, amotivation, and social withdrawal), cognitive and motor symptoms similar to those seen in naturally-occurring schizophrenia. Behaviors elicited by MK-801 in mice reflect a pharmacologically-induced state of NMDA receptor hypofunction (NRH), which has been proposed to exist in schizophrenia. Compounds that attenuate MK-801-elicited behaviors, which are identified in this animal model, may have the potential to treat schizophrenia, including deficit and cognitive symptoms. In the current study, anabasine attenuated MK-801-elicited popping at a dose that did not cause clonic seizures. The development of alpha7-nicotinic acetylcholine receptor agonist interventions for schizophrenia must consider their potential liability to elicit seizure activity.
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PMID:Anabasine, a selective nicotinic acetylcholine receptor agonist, antagonizes MK-801-elicited mouse popping behavior, an animal model of schizophrenia. 1526 37

NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.
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PMID:Exogenously administered D-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice. 1661 33


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