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)

We measured [125I] iomazenil binding, labeling the central-type benzodiazepine receptor in 37 discrete rat brain areas following single (7.5 mg/kg, i.p.) and repeated (7.5 mg/kg/day x 14 days, i.p.) treatment with phencyclidine (PCP), a non-competitive antagonist of the N-methyl-D-aspartate(NMDA)-type glutamate receptor, using in vitro quantitative autoradiographic receptor binding assay. Both single and repeated PCP treatment produced heterogeneous changes in the rat brain in a similar manner, the magnitude of change in [125I] iomazenil binding being generally greater in the repeated treatment group than in the single treatment group. A significant increase in [125I] iomazenil binding was observed in the superficial layer (layer I-IV) of the parietal cortex in both of the PCP treatment groups and the CA1 of the hippocampus of the repeated PCP-treated group. There was a significant decrease in [125I] iomazenil binding in the piriform cortex of the repeated PCP-treated group. These results suggest that the blockade of NMDA receptor-mediated glutamatergic neurotransmission by PCP produces the compensational alterations in the central-type benzodiazepine receptor antagonist binding, and that the observed diversity may be due to dissimilar modes of organizations between glutamatergic and the GABA(gamma-aminobutyric acid)-benzodiazepine receptor complex.
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PMID:The effects of single and repeated phencyclidine administration on [125I] iomazenil binding in the rat brain. 888 87

The relationship between hippocampal electrical activity and behavioral hyperactivity induced by either phencyclidine (PCP) or methamphetamine (MAP) was examined in freely behaving rats. The EEGs at the hippocampal CA1 region were simultaneously recorded with the animal's behavior for 2 h after administration of either PCP or MAP. PCP (10 mg/kg, intraperitoneal (i.p.)) significantly increased locomotor activity including rearing, walking, head-weaving and circling. Spectral analysis of the EEG showed that hippocampal gamma waves (30-70 Hz), but not other frequency bands, were significantly increased from 5 to 120 min after systemic injection of PCP. Inactivation of the medial septum with muscimol, a gamma-aminobutyric acid receptor A agonist, 15 min prior to injection of PCP, suppressed both hippocampal gamma waves and locomotor activity. MAP (1.5 mg/kg, i.p.) also increased locomotor activity for longer than 2 h. During the behavioral hyperactivity induced by MAP, hippocampal EEG showed θ and gamma rhythms that were not significantly different from those during walking before MAP. However, MAP-induced behavioral activity was suppressed by pre-injection of muscimol in the medial septum, which also decreased hippocampal gamma activity. It is suggested that the medial septum plays a role in mediating behavioral disturbances induced by both PCP and MAP through control of the hippocampal electrical activity, and that hippocampal gamma waves may play a permissible role in the expression of behaviors.
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PMID:Relation between hippocampal gamma waves and behavioral disturbances induced by phencyclidine and methamphetamine. 1084 Jan 27

Recent biochemical observations have suggested the abnormalities in the gamma-amino-butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABA(A) receptor following acute and chronic administration of phencyclidine (PCP), which induces schizophrenia-like symptoms, in rats using in situ hybridization and in vitro quantitative autoradiography. PCP i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of alpha 1 subunit mRNA in cerebral cortices (cingulate (-13%) and temporal cortex (-6%)) and hippocampal formation (CA1 (-11%), CA2 (-10%), CA3 (-11%) and dentate gyrus (-12%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of beta 2 mRNA in the cerebellum (-10%) and of beta 3 mRNA in the cerebral cortices (cingulate (-12%), parietal (-16%) and temporal cortex (-16%), caudate putamen (-18%), inferior colliculus (-18%), and cerebellum (-15%) were significantly decreased. In addition, [(35)S]t-butylbicyclophosphorothionate (TBPS) binding was also reduced in layer IV of the frontoparietal cortex (-14%), inferior colliculus (-17%), and cerebellum (-12%) following chronic PCP treatment, while no changes were observed following acute PCP treatment. These results indicate that single and repeated administrations of PCP independently regulate the expression of GABA(A)/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain.
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PMID:Differential expression of GABA(A) receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration. 1094 Nov 40

Recent animal studies regarding phencyclidine (PCP), which induces psychotic symptoms in humans, have suggested that group II metabotropic glutamate receptors (mGluRs) represent a novel target for the treatment of PCP psychosis. In the present study, we used in situ hybridization to investigate the gene expressions of the mGluR 1-5 subtypes following single and repeated administration of PCP in rats. A single administration of PCP (7.5mg/kg, i.p.,) resulted in a significant decrease in the mGluR5 mRNA expression of group I mGluR in the subcortical regions (thalamus (-15%), central gray (-23%), inferior colliculus (-23%), and nucleus accumbens (-10%)) and hippocampal formation (CA1 (-14%), CA2 (-15%), CA3 (-18%), and dentate gyrus (-18%)). After repeated PCP administration for 14 days, the mGluR2 mRNA expression of group II mGluR in the anterior cingulate cortex (-23%) and the mGluR4 mRNA expression of group III mGluR in the cortical regions (parietal (-11%), temporal (-13%) and entorhinal cortices (-18%)), the caudate putamen (-12%), thalamus (-17%), and subiculum (-25%) were significantly decreased. These results indicate that PCP affects not only group II mGluR but also group I and III of mGluR, and it is of particular interest that mGluR2 subtype is involved in a development of behavioral abnormality following repeated PCP administration. Single and repeated administrations of PCP independently regulate the expression of mGluR subtypes of mRNA in the brain.
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PMID:Effects of single and repeated phencyclidine administration on the expression of metabotropic glutamate receptor subtype mRNAs in rat brain. 1142 1

ATP hydrolysis is critical for many cellular processes; however, the acute requirement for ATP hydrolysis in synaptic transmission and plasticity in neurons is unknown. Here we studied the effects of postsynaptically applying the non-hydrolyzable ATP analogue adenosine 5'-[beta,gamma-methylene]triphosphate (AMP-PCP) into hippocampal CA1 pyramidal cells in hippocampal slices. The effects of this manipulation were investigated on basal transmission and on two forms of long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD). AMP-PCP caused an increase in basal AMPA receptor (AMPAR)-mediated transmission, which occurred rapidly within minutes of infusing the drug. This effect was selective for AMPARs, since pharmacologically isolated NMDAR-mediated synaptic currents did not exhibit this run up. In two-pathway experiments infusion of AMP-PCP blocked the induction of both LTD and LTP. These findings show an acute and selective role for ATP hydrolysis in regulating AMPAR function both during basal transmission and long-term synaptic plasticity. Recent evidence indicates that AMPARs are selectively and acutely regulated by the ATPase N-ethylmaleimide-sensitive factor (NSF), which forms part of a multi-protein complex with AMPARs. Our data are consistent with the idea that such a mechanism that can acutely bi-directionally regulate AMPAR function at synapses and requires ATP hydrolysis is necessary for rapid activity-dependent changes in synaptic strength.
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PMID:ATP hydrolysis is required for the rapid regulation of AMPA receptors during basal synaptic transmission and long-term synaptic plasticity. 1585 21

Using whole-cell voltage-clamp recordings, hyperpolarization-activated cation currents (Ih) were elicited with hyperpolarizing voltage jumps in CA1 pyramidal neurons of rat hippocampal slices, and the effects of phencyclidine (PCP) and some sigma ligands on Ih were studied. PCP concentration-dependently (0.1-100 microM) suppressed Ih and shifted the activation curve of Ih to the negative direction. D-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 20 microM) and MK-801 (30 microM), competitive and non-competitive NMDA blockers, respectively, failed to mimic the inhibitory effect of PCP on Ih, and suppression of Ih by PCP was unaffected in the presence of these blockers. To explore the involvement of sigma1 receptors in the reduction of Ih, the effects of representative sigma1 ligands were studied. SKF10047 (100 microM), a sigma1 agonist, attenuated the maximal Ih and shifted the half-activation potential of Ih to the hyperpolarized direction. In the presence of the sigma1 antagonist NE-100 (1 microM), which alone did not affect Ih, the effect of SKF10047 on Ih was unaltered. By contrast, a higher concentration of NE-100 (10 microM) mimicked the effect of SKF10047. Again, no antagonism of Ih suppression by SKF10047 was obtained with rimcazole (100 microM), a sigma1 receptor antagonist that is structurally distinct from NE-100. This concentration of rimcazole alone resulted in a slight but significant reduction of Ih. Thus these major sigma1 ligands appear to suppress Ih independently of their agonistic or antagonistic properties. The results of this study suggest that PCP and some sigma ligands could modulate cell excitability partly through their action on Ih.
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PMID:Inhibition of hyperpolarization-activated cation currents by phencyclidine and some sigma ligands in rat hippocampal CA1 pyramidal neurons in vitro. 1763 22

Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4h after a single injection of PCP. We used receptor autoradiography and [3H]MK801, [3H]AMPA, [3H]pirenzepine and [3H]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F=14.5, d.f.=1, p<0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippocampus CA1 (-16%), hippocampus CA2 (-25%), dentate gyrus (-27%), parietal cortex layers III-VI (-19%), central nucleus of the amygdala (-40%), and basolateral amygdala (-19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions.
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PMID:Rapid cortico-limbic alterations in AMPA receptor densities after administration of PCP: implications for schizophrenia. 1864 Feb 63

Persistent blockade of NMDA receptor function by repeated phencyclidine dosing produces pathophysiological changes that model deficits observed in schizophrenia. The present study investigates the effects of subchronic phencyclidine administration (PCP; 2 or 5mg/kg bi-daily for 7 days followed by a drug-free period) on sucrose choice, a measure of anhedonia. Sucrose preference in a two-bottle sucrose-water choice test was assessed 1 and 2 weeks after PCP. Results showed no differences in sucrose intake between PCP rats and controls, nor a difference in water intake or total volume of liquid consumed at either time-point. Six weeks post-PCP, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and CA2/3 regions. These results demonstrate that while subchronic PCP may not be a valid model for the negative symptom of anhedonia observed in schizophrenia, it induces pathology in the brain in hippocampal subregions that are reminiscent of changes observed in schizophrenia.
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PMID:Effect of subchronic phencyclidine administration on sucrose preference and hippocampal parvalbumin immunoreactivity in the rat. 2009 62

Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p<0.05), motor cortex (p<0.01), orbital cortex (p<0.01), olfactory bulb (p<0.05), retrosplenial cortex (p<0.001), frontal cortex (p<0.01), parietal cortex (p<0.01), CA1 (p<0.05) and polymorphic layer of dentate gyrus (p<0.05) of the hippocampus and the central (p<0.01), lateral (p<0.05) and basolateral (p<0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p<0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.
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PMID:Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain. 2085 70

Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories.
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PMID:Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia. 2208 80


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