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)

Long-term potentiation (LTP) of synaptic transmission in the rat hippocampus in vivo and in vitro, was studied using field potentials. Pretreatment with phencyclidine (PCP) or 'sigma' opiates blocked LTP in vivo while mu and kappa opiates and the antagonist naloxone were ineffective. Scopolamine (20 mg/kg i.p.) neither prevented LTP nor antagonized the LTP-blocking effect of PCP. In vitro, PCP up to 100 microM did not alter synaptic activation of CA1 pyramidal cells by stratum radiatum stimulation but blocked LTP in a dose-dependent manner (ED50: 3 microM). The sigma opiate, cyclazocine, also prevented the induction of LTP in vitro while morphine and procaine were ineffective.
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PMID:Blockade of long-term potentiation by phencyclidine and sigma opiates in the hippocampus in vivo and in vitro. 631 41

The effects of local application of phencyclidine (PCP) upon hippocampal CA1 neurons were investigated in urethane-anesthetized rats. Hippocampal neurons were classified on the basis of extracellularly recorded action potential duration as either complex-spike or theta cells prior to PCP administration. PCP depressed spontaneous firing of 46 of 48 complex-spike cells, but excited 12 of 13 theta neurons. This result demonstrates that hippocampal complex-spike and theta neurons may be differentiated of theta neurons were greatly attenuated or absent in rats pretreated with DSP4, a neurotoxin which selectively destroys noradrenergic pathways. This latter finding lends additional support to the hypothesis that the effects of locally applied PCP are mediated via noradrenergic mechanisms.
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PMID:Differential effects of phencyclidine upon hippocampal complex-spike and theta neurons. 632 73

Phencyclidine (PCP) and several behaviorally active or inactive structural analogs were administered i.v. to urethane-anesthetized rats in order to determine their effects on CA1 pyramidal cell discharges elicited by contralateral CA3 (cCA3) stimulation. PCP and the behaviorally active m-amino derivative (m-NH2 PCP) depressed, in a dose-dependent manner, the amplitude of the population spike evoked in CA1 by a cCA3 stimulation (ED 50s: 0.9 mg/kg for PCP, 0.5 mg/kg for m-NH2 PCP). However, the behaviorally inactive derivatives m-nitro (m-NO2 PCP) and PCP methyliodide (PCP CH3I) were ineffective up to 10 mg/kg. PCP (0.1-0.3 mg/kg i.v.) also decreased the duration of inhibition of CA1 discharges in a paired-stimulus paradigm; this was in contrast to the effects of thiopental and diazepam. In midcollicular-transected, urethane-anesthetized rats, the inhibitory effect of PCP on cCA3-CA1 transmission was not observed but the drug was still as effective as in intact rats in the paired-stimulus paradigm. In animals subjected to 6-hydroxydopamine lesions of the hippocampal noradrenergic innervation (average 85%) decrease in NE content), the potency of PCP in inhibiting cCA3-CA1 transmission was the same as in a group of sham-operated controls. These results suggest the following conclusions: (i) PCP exerts at least 2 separate types of effects in CA1, both of which result from a central action of the drug; (ii) PCP decreases the monosynaptic excitation of CA1 pyramidal cells and this action requires the integrity of brainstem afferents; (iii) PCP may decrease recurrent inhibition or afterhyperpolarization in CA1 via a mechanism which is independent of these connections and, therefore, could result from a direct action of the drug at the level of the hippocampus; (iv) finally, no evidence was found to suggest that the noradrenergic innervation of the hippocampus is critically involved in the action of PCP on CA1 discharges.
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PMID:Effect of phencyclidines on hippocampal pyramidal cells. 681 48

Since the hippocampus is likely to be a major site of phencyclidine (PCP) action, the effects of various doses of PCP (1.8, 18 or 36 nM) as well as 3.6 nM MK-801 or saline injected directly into the dentate gyrus of the hippocampus was tested for acquisition of a spatial navigation task (dry land version of a water maze) using a paradigm that assesses short term memory based on learning within a day and long term memory based on learning between days. Results indicated that relative to saline or 1.8 nM PCP injected rats, rats with 18 or 36 nM PCP or 3.6 nM MK-801 injections were impaired in acquisition of the task as measured by increased distances traveled to find the food location between days but not within days. In additional experiments 36 nM PCP or 3.6 nM MK-801 did not produce any deficits in the acquisition of an object discrimination task. It is suggested that PCP through its blocking action of the NMDA receptor in the dentate gyrus or CA1 region of the dorsal hippocampus mediates the consolidation of new spatial location information.
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PMID:Phencyclidine injections into the dorsal hippocampus disrupt long- but not short-term memory within a spatial learning task. 748 May 53

Binding of a novel radioligand, [3H]3-OH-PCP (1(1(3-hydroxyphenyl) cyclohexyl)piperidine), to N-methyl-D-aspartate (NMDA) receptor-coupled and -uncoupled PCP sites was investigated in the rat brain. The highest densities of [3H]3-OH-PCP binding were observed in the hippocampal formation, notably in the stratum radiatum and oriens of CA1 region, and dentate gyrus. There were relatively high levels of binding in the olfactory system, superficial layer of cortices, the amygdala and the thalamus. In contrast, lower levels of binding were found in the globus pallidus, cerebellum, and brain stem, except for the superior colliculus. These findings demonstrate that [3H]3-OH-PCP binds to discrete regions within the rat brain. Its distribution is consistent with autoradiographic localization of [3H]TCP and [3H]MK-801 binding sites in the rat brain, suggesting that [3H]3-OH-PCP binds to NMDA/PCP ion-channel complexes in preference to sigma sites.
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PMID:Quantitative autoradiographic localization of [3H]3-OH-PCP (1-(1(3-hydroxyphenyl)cyclohexyl)piperidine) binding sites in rat brain. 762 Sep 17

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

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

Phencyclidine (PCP) is a psychotomimetic drug associated with acute and delayed mental effects in normal humans and psychosis exacerbation in already psychotic schizophrenic individuals. We have previously described a dose-sensitive, delayed action of PCP on regional cerebral metabolism in the rat which occurs over 48 hours and a late (24 hour) change in N-methyl-d-aspartate (NMDA) and kainate binding in hippocampal areas. Now, we report the complex time course of PCP action on NMDA-sensitive glutamate receptor binding in rat in distinct subregions of the hippocampus extending over 48 hours. Selectively, in the hippocampal CA1 region, a single dose of PCP (8.6 mg/kg) produced an increase in receptor binding at 12 hours (+24%), sustained to 24 hours (+29%) compared with the 3 hour post-PCP value (-15%) and then a return to control levels of receptor binding at 48 hours. Other regions of hippocampus showed distinctive time-dependent changes in NMDA-sensitive glutamate receptor binding as well. In addition, PCP produced a change in kainate receptor binding in the dentate gyrus across the 48-hour time period. In other representative brain regions, PCP did not alter NMDA or kainate binding over the same time course. This extended neurochemical effect of PCP on glutamate receptors in rat hippocampus parallels, in time, certain delayed psychological actions of PCP in humans and thus may be relevant to psychosis, especially to PCP-induced psychosis.
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PMID:Phencyclidine produces changes in NMDA and kainate receptor binding in rat hippocampus over a 48-hour time course. 885 12

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

The pharmacological characteristics and the regional distribution of [3H]3-OH-PCP (1-[1(3-hydroxyphenyl)-cyclohexyl]piperidine) binding were investigated in rat brain by quantitative autoradiography. Kinetic analysis of [3H]3-OH-PCP binding revealed fast and slow components, in the association and dissociation studies. The regional distribution of binding closely corresponded to those of binding sites labeled by [3H]N-[l-(2-thienyl)-cyclohexyl]3,4-piperidine (TCP) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate (MK 801). High densities of [3H]3-OH-PCP binding sites were found in the stratum radiatum and orients of field CA1 in the hippocampus and in the outer layers of cerebral cortices. In contrast, low levels of binding were seen in the brain stem and the granular cell layer of the cerebellum. [3H]3-OH-PCP binding was strongly inhibited by MK 801 and 3-OH-PCP, while the potency of (+)-SKF 10047 in inhibiting [3H]3-OH-PCP binding was less in the cerebral cortex and hippocampus. The antagonists for the glutamate, glycine and polyamine recognition sites at the NMDA/PCP receptor complex displaced [3H]3-OH-PCP binding sites with a potency similar to that of [3H]MK 801. These findings suggest that the [3H]3-OH-PCP binding site is similar or identical to the PCP binding site labeled by [3H]TCP and [3H]MK 801.
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PMID:Autoradiographic study on the pharmacological characteristics of [3H]3-OH-PCP binding sites in rat brain. 888 23


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