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)

Frontal-subcortical circuits provide a comprehensive framework for understanding the anatomy, biochemistry, and pharmacology of behavior. The three principal behaviorally relevant circuits originate in the dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex, respectively. Circuit-specific marker behaviors associated with each circuit are executive dysfunction (dorsolateral prefrontal-subcortical circuit), disinhibition and OCD (orbitofrontal-subcortical circuit), and apathy (medial frontal-subcortical circuit). Environmental dependency is common to all prefrontal-subcortical syndromes and may reflect disruption of working memory. Depression, mania, and psychosis are mediated by structures involved in prefrontal-subcortical circuits and are circuit-related but not circuit-specific behaviors. The actions of PCP, LSD, serotonergic antidepressants, anxiolytics, sedative-hypnotics, antipsychotic agents, and ethanol may all be partially or primarily mediated through transmitter systems and receptor effects expressed through frontal-subcortical circuits.
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PMID:Anatomic and behavioral aspects of frontal-subcortical circuits. 859 19

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

The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) is a psychotomimetic drug which produces schizophrenia-like psychosis. In animal studies it is toxic to neurons in the posterior cingulate and retrosplenial cortex and to cerebellar Purkinje cells. To find clues about the mechanism and pathways of PCP action, we studied the effect of systemic PCP administration (10 and 50 mg/kg, intraperitoneal) on the expression of immediate-early genes (IEGs) (c-fos, c-jun, egr-2, egr-3, NGFI-A, NGFI-B, NGFI-C, and Nurr1) using in situ hybridization histochemistry. PCP, 50 mg/kg, produced a biphasic IEG induction: an early induction in the hippocampus, cerebral cortex, and cerebellar granule cell layer, and a delayed induction in the posterior cingulate cortex and cerebellar Purkinje cell layer. The early induction of all eight IEGs was observed 30 min after drug treatment in the cerebral cortex and in the hippocampus. c-fos, NGFI-A, and NGFI-B were also induced in thalamic nuclei, and c-fos was also induced in the cerebellar granule cell layer. In contrast, a delayed induction of c-fos, c-jun, NGFI-A, NGFI-B, NGFI-C, and Nurr1 in the posterior cingulate cortex was observed 2-6 hr after PCP, 50 mg/kg. egr-2 and egr-3 were not induced in the posterior cingulate cortex. c-fos induction in the cerebellar Purkinje cell layer peaked 2 hr after PCP, 50 mg/kg. In addition, PCP induced c-fos, egr-3, NGFI-A, NGFI-B, NGFI-C, and Nurr1 in the inferior olivary nucleus. PCP-induced IEG expression returned to baseline by 24 hr. A lower PCP dose, 10 mg/kg, induced lower levels of IEG expression, with similar anatomical and biphasic temporal pattern as with the higher PCP dose of 50 mg/kg. However, no IEG induction was observed in the hippocampus following 10 mg/kg PCP. These results demonstrate that PCP produces neural activation not only in the cingulate and retrosplenial cortex, but also in many other regions of forebrain and cerebellum. Moreover, prolonged IEG expression in the posterior cingulate cortex and cerebellar Purkinje cells, the sites of PCP toxicity, suggests that IEGs could mediate neurotoxic/neuroprotective effects in these brain regions.
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PMID:Effects of phencyclidine on immediate early gene expression in the brain. 881 9

Phencyclidine (PCP) produces a psychotic reaction in humans which closely resembles an acute episode of schizophrenia and has therefore been given an increasing amount of attention as a model for schizophrenia. The present article reviews the behavioral and neurochemical effects of PCP in both humans and animals. Where possible, comparisons are made between the effects of PCP and amphetamine. The merits of the dopamine versus NMDA/PCP receptor mediated expression of PCP-induced psychosis are discussed, as well as the importance of selecting behavioral models which are best suited to model the expression of psychosis, rather than the motor effects of psychotomimetics.
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PMID:The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis. 885 14

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

Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their functional importance in mental activity is considerable. Therefore, the involvement of this neurotransmitter in the pathology of schizophrenia is being studied. Biochemical evidence has suggested that glutamatergic transmission may be regionally reduced in schizophrenia, although this evidence has never been completely consistent nor fully replicable. More striking has been the behavioral effects in humans of the antiglutamatergic drugs phencyclidine (PCP) and its congener ketamine. By historical report, PCP produces a 'schizophrenia-like' psychosis in normal humans and aggravates the psychosis in schizophrenics. More recently, ketamine has been shown to produce a mild psychotomimetic effect in normal volunteers, which has some schizophrenia-like features. We have studied the effects of ketamine in schizophrenic patients. Here, ketamine intensified each patient's specific underlying psychosis, an effect not blocked by haloperidol. Moreover, ketamine selectively increased cerebral blood flow (CBF) in the anterior cingulate cortex and reduced CBF in hippocampus and lingual gyrus. These data may be pertinent to the subject's psychosis exacerbation, especially because both cingulate and hippocampus have been previously implicated in schizophrenic psychosis. In addition, ketamine produced a distinctive dynamic time-course of regional CBF changes in different anatomic regions, with immediate (5-10 min) changes in cingulate, but somewhat more delayed changes (20-40 min) in the thalamus and cerebellum. Our immediate early gene (IEG) time-course data with c-fos and zif268 in rats following PCP suggest that a single dose of this antiglutamatergic compound can have an effect in some brain areas which lasts beyond 48 h, an effect which is distinct by IEG and by region. Together, these data suggest that glutamate-mediated neurotransmission has a strong influence in schizophrenia, although the specifics of this involvement have yet to be articulated.
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PMID:Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. 886 63

Phencyclidine (PCP) can induce a model psychosis which has a number of similarities to dementias and schizophrenia. In some cases the psychosis persists for prolonged periods after drug discontinuation. N-Methyl-D-aspartate (NMDA) antagonists such as PCP induce increases in glucose metabolism in a variety of brain structures but most notably in limbic regions such as retrosplenial, piriform, and entorhinal cortex, hippocampus, and olfactory tubercle. When given continuously for several days, these NMDA antagonists induced neural degeneration in these same critical limbic areas. In the present study regional 2-fluorodeoxyglucose (FDG) uptake was measured in rats at both 24 h and 10 days after neurotoxic, 5-day "binge" PCP administration. At 24 h after minipump removal there were persisting and large increases in glucose uptake in many brain regions, with maximal changes in the same limbic structures in which neurotoxicity has been observed. Surprisingly, many of these regions still showed elevated glucose metabolism after 10 days of recovery. These findings suggest an anatomical and neurochemical substrate for the persisting psychosis which can occur following PCP.
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PMID:Persisting changes in brain glucose uptake following neurotoxic doses of phencyclidine which mirror the acute effects of the drug. 887 27

Phencyclidine (PCP) and amphetamine (AMP) can induce psychotic syndromes in humans, whereas administration of these drugs to mice results in behavioral activation that is influenced by genetic factors. Quantitative trait loci (QTL) underlying genetic differences in response to PCP and AMP in mice were provisionally identified by correlating allelic variation at known marker loci in the BXD series of recombinant inbred (RI) mice and its progenitors (C57BL/6J and DBA/2J inbred strains) with the locomotor response of each strain to PCP and AMP. Total distance traveled for individual mice from each of the 26 BXD RI and two progenitor strains was measured after injections of normal saline and 7.5 mg/kg i.p. injection of PCP. This procedure was repeated after 1 week, using 5.0 mg/kg of AMP, instead of PCP. Markers significantly (p < .01) correlated with response to PCP map to murine chromosomes 1, 14, and 15. Response to amphetamine was correlated with markers mapping to chromosomes 4, 5, 6, 8, 14, and 18. Identification of the QTL underlying PCP-induced and AMP-induced behavior in mice may provide clues into the complicated genetics of psychosis in humans.
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PMID:Quantitative trait loci contributing to phencyclidine-induced and amphetamine-induced locomotor behavior in inbred mice. 891 21

Calcitonin gene-related peptide (CGRP) is the major product of the calcitonin gene in brain and exerts a number of actions in the central nervous system (CNS). In particular the finding that CGRP affects dopamine (DA) release and metabolism has raised the possibility that it may play a role in several neuropsychiatric disorders. Consequently, we have here studied the effects of two psychotomimetic drugs, namely, d-amphetamine (AMPH) and phencyclidine (PCP), on CGRP concentrations in brain microdialysates from freely moving rats. The animals were stereotaxically implanted with vertical concentric probes in the medial prefrontal cortex (mPFC), the ventral striatum (vSTR), or the hippocampus; and the experiments were performed 48 hr after surgery. The dialysis probes were perfused with a modified Ringer's solution at the rate of 5 microliters/min. AMPH 1.5 mg/kg, PCP 2.5 mg/kg, or NaCl 0.9% were injected s.c.; and the perfusates were collected at 60 min intervals before and after the injections and used for CGRP-like immunoreactivity (-LI) determination by radioimmunoassay (RIA). In separate experiment, KCl (100 mM), veratridine (50 microM), or tetrodotoxin (2 microM), were added to the perfusate and infused in the vSTR. Baseline levels of CGRP-LI were detected in dialysates from all three regions. Both AMPH and PCP caused a significant and sustained increase (maximum about 300%) in CGRP-LI concentrations, in particular from the mPFC and vSTR, while saline had no effect. KCl and veratridine also increased CGRP-LI in dialysates during the first posttreatment period, while tetrodotoxin induced a significant but delayed decrease in CGRP-LI levels. Finally, cervical dislocation also elevated CGRP-LI in dialysates from the mPFC and the vSTR. Our findings demonstrate that 1) CGRP-LI can be measured in vivo in microdialysates from mPFC, vSTR, and hippocampus; 2) the release in vSTR is action potential-dependent; and 3) systemic administration of AMPH or PCP results in a long-lasting release of CGRP-LI in the mPFC and vSTR, thus demonstrating a novel action of these drugs in the brain. Since other studies have shown that major antipsychotic drugs appear to reduce CGRP release in brain, our study provides, in principle, support for a role of CGRP in psychotic disorders.
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PMID:The psychotomimetic drugs D-amphetamine and phencyclidine release calcitonin gene-related peptide in the limbic forebrain of the rat. 893 70

Phencylidine (PCP) is a psychotomimetic noncompetitive glutamate antagonist that has been used in studies of the neural substrates of psychosis. Both schizophrenic patients and PCP-treated rats exhibit reduced amounts of prepulse inhibition (PPI) of the startle reflex, which is the normal inhibition of startle that occurs when the starting noise is preceded 30 to 500 msec by a weak prepulse. The present study assessed the effects of seroquel (ICI 204,636), a mixed D2/5-hydroxytryptamine2 antagonist with a preclinical profile suggestive of potential antipsychotic efficacy, on the PCP-induced disruption of PPI. Clozapine, risperidone and haloperidol were also studied as comparison compounds. PCP (1.25 mg/kg) significantly reduced PPI, with prepulses that were 1 to 12 dB above background. Seroquel and clozapine significantly restored PPI in PCP-treated rats, whereas haloperidol and risperidone did not. Similar findings were obtained in studies using separate animals, a slightly lower dose of PCP (1.0 mg/kg) and a high dose of each of these antipsychotics. Separate studies verified that risperidone and haloperidol restored PPI in apomorphine-treated rats. In the present studies, seroquel exhibited a profile consistent with those exhibited by other "atypical" antipsychotics.
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PMID:Seroquel restores sensorimotor gating in phencyclidine-treated rats. 896 53


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