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)

PCP and its new metabolites persisted for very prolonged periods in rat brain and adipose tissue after a single 25 mgkg-1 intraperitoneal injection and showed accumulation after multiple dosing. The brain to plasma ratios for PCP between 0.5 h to 48 h after injection ranged between 6 to 8.8 and adipose tissue to plasma ratios between 31 to 113. The concentrations of metabolites of PCP in rat brain (ng-eqt/g. tissue) 1, 2 and 3 weeks after a single 25 mgkg-1 i.p. injection of PCP were approximately 390, 230 and 74 respectively and those of PCP 12, 6 and 5 ng/g. respectively. The long sojourn of PCP in adipose tissue and relatively slow egress therefrom explains cumulative effects upon multiple dosing and raises the possibility of mobilisation or release of large amounts of drug from fat stores in situations involving food deprivation, marked weight loss or stress. The persistence of PCP and its metabolites in brain and high degree of binding with melanin, implying a possible localisation in neuromelanin-rich substantia nigra of midbrain and locus coeruleus of pons may help explain the prolonged duration of clinical effects and persistent neurological and cognitive dysfunction several days after PCP administration.
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PMID:Persistence of phencyclidine (PCP) and metabolites in brain and adipose tissue and implications for long-lasting behavioural effects. 45 33

Phencyclidine (PCP), in a dose of 15 mg/kg, produced delayed cognitive dysfunction (at 24 h) in rats subjected to water maze tasks. At 24 h after PCP administration, ataxia, hyperlocomotion and stereotyped behavior were not induced. NE-100, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-enthylamine monohydrochloride, a selective and potent sigma receptor ligand, was administered orally 10 min after PCP administration or 15 min before the first trial (24 h after PCP administration). In both cases, NE-100 dose-dependently attenuated the delayed cognitive dysfunction induced by PCP. As these findings show that ingestion of PCP led to delayed cognitive dysfunction similar to the cognitive signs of psychosis seen in humans, NE-100 is being further studied for possible treatment of subjects with schizophrenia.
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PMID:Effect of NE-100, a novel sigma receptor ligand, on phencyclidine- induced delayed cognitive dysfunction in rats. 760 28

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a selective and potent sigma receptor ligand. We investigated the effects of NE-100 on phencyclidine (PCP)-induced cognitive dysfunction in rats in a water maze task. NE-100 significantly shortened the PCP-induced prolonged swimming latency as did 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine monohydrobromide (Dup 734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1-(cyclopropyl-methyl)pi peridine (XJ 448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole, all of which are sigma receptor ligands and possibly antagonists. Ritanserin, a 5-HT2 receptor antagonist, also showed a tendency to shorten swimming latencies. Latencies of haloperidol-, cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4-met hyl- aminobenzamide (YM-09151-2)- and sulpiride-, dopamine D2 receptor antagonists, treated groups did not differ from that seen in the PCP-treated group. Thus, PCP-induced cognitive dysfunction may be improved by sigma receptor ligands.
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PMID:Effect of NE-100, a novel sigma receptor ligand, on phencyclidine-induced cognitive dysfunction. 782 67

Clinical evidence of methamphetamine (MAP)-induced reverse-tolerance phenomenon is available in studies of methamphetamine psychosis. To examine the clinical relevance of the reverse-tolerance phenomenon as a model of this psychosis, two experiments were conducted using rats. In the first experiment, we examined the relationship of MAP (4 mg/kg/day)-induced reverse tolerance in behavioral stereotypy to impairment of the cliff avoidance reaction (CAR). The stereotypy scores by the method of Creese and Iversen reached a maximum at day 14, and were unchanged thereafter. Impairment of CAR appeared in 3 of 6 rats at day 21 or 28 without motor ataxia, as rated by the scoring system of Hiramatsu et al. This suggested that cognitive dysfunction reflected by CAR impairment may develop after MAP-induced reverse-tolerance phenomenon, as evaluated by the behavioral stereotyping rating scale. In the second experiment, the effect of PCP (1 mg/kg) on CAR was examined in rats pretreated with MAP (4 mg/kg/day) for 30 days. No behavioral stereotypy or CAR impairment was found in these rats for 1 hour after PCP challenge. This showed that MAP-induced reverse-tolerance did not alter sensitivity to PCP in producing behavioral stereotypy or CAR impairment.
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PMID:[Reverse-tolerance phenomenon in methamphetamine-induced behavioral stereotypy and impairment of cliff avoidance reaction after subchronic methamphetamine administration in rats]. 856 32

Acute administration of phencyclidine to rats potently activates mesocorticolimbic dopaminergic neurons. The activation of dopamine release and utilization in the prefrontal cortex and nucleus accumbens are associated with profound cognitive impairment and hyperlocomotion, respectively. This dopaminergic activation by phencyclidine is not mediated by direct effects on the cell body regions of the dopamine neurons; however, phencyclidine augments dopamine release locally in the terminal fields. In the present study, the possible involvement of the prefrontal cortex in mediating activation of the mesolimbic dopamine system by phencyclidine was examined. Ibotenic acid lesions of the prefrontal cortex attenuated the biochemical activation of the mesolimbic dopamine neurons by PCP, and prefrontal lesions sharply blunted phencyclidine-, but not amphetamine- or novelty-, induced hyperlocomotion. In addition, injection of phencyclidine directly into the prefrontal cortex increased dopamine utilization in the nucleus accumbens and induced hyperlocomotion. In summary, these studies show that phencyclidine activates the mesolimbic pathway through a mechanism in the prefrontal cortex, possibly by disinhibiting the cortical circuit and activating corticofugal glutamatergic release in the ventral tegmental area.
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PMID:Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence. 969 31

Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.
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PMID:Dextromethorphan and dextrorphan in rats: common antitussives--different behavioural profiles. 979 51

D4 dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopaminergic systems appear to be involved in modulating some cognitive functions of the prefrontal cortex. Despite anatomical localization of D4 DRs within the frontal cortex, the role of these receptors, specifically, in the regulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D4 DRs would affect performance of a task dependent on the frontostriatal system. The effects of NGD94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazol e dimaleate), a potent and selective D4 DR antagonist and haloperidol, a non-specific D2-like DR antagonist, on the performance of an object retrieval/detour task by monkeys were examined. The effects of these antagonists on the object retrieval task were evaluated in normal control monkeys and in subjects repeatedly exposed to phencyclidine (PCP), to induce frontal cortical dopaminergic and cognitive dysfunction. NGD94-1 (1-5 mg/kg) reversed the cognitive deficits of PCP pre-treated monkeys, whereas haloperidol (25 microg/kg) exacerbated PCP-induced performance impairments. A low dose of NGD94-1 failed to affect performance of control subjects, while both haloperidol and a high dose of NGD94-1 impaired control performance. These data show, for the first time, that D4 DRs modulate the cognitive functions of the frontostriatal system.
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PMID:Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. 1010 86

Predictors of non-response were investigated in a 15-year follow-up (1981-1996) of 3,481 individuals in a probability sample from the household population of East Baltimore. Demographics (age, sex, race, education, marital status, and unemployment), household factors (living arrangements, household income, household size, and number of children), cultural variables (ancestral ethnicity and foreign language), social variables (social support and networks, committing felony, carrying a weapon, using an alias, and wandering), health factors (physical illness, health insurance, medical assistance, Medicare, receiving disability benefits, social security, and welfare), interviewer's observation, and psychopathologic variables (mental disorders, suicide behavior, comorbidity, and drug use) were collected at baseline in 1981 and in 1982, then linked to follow-up data between 1993 and 1996. A tracing process involving mail, phone, criss-cross directories, motor vehicle administration records, a commercial credit bureau, the state criminal justice system, hospital records, the US National Death Index, and field tracing were used to locate the original sample. A total of 3,066 respondents of the original sample (88.1%) were traced. Non-response was categorized into Sample Mortality (that part of the original sample that died during follow-up), Sample Loss (that part of the original sample that survived but could not be found) and Refusal (that part of the original sample that survived and was found but refused to participate). Stratified analysis and adjusted multiple logistic regression modeling found sample mortality and sample loss were strongly influenced by individual and household variables and by psychopathology. Sample mortality was influenced by specific mental disorders or conditions as mania, drug abuse/dependency, antisocial personality, cognitive impairment, alcohol abuse/dependency, phobia, drug use (except PCP), and comorbidity. Household factors protective against mortality include higher household income, not living as extended members in a married couple family, and living with children in the household. Persons who were unemployed, widowed or single, without high school education, male, and 65 years of age or older were more likely to die. Sample loss was influenced by cognitive impairment, antisocial personality, and cocaine use. Household factors linked to sample loss include living in female-headed families, or non-family households, and living alone. Young nonwhite, divorced/separated, without high school education, and unemployed were also harder to find. Refusal was associated with being white, with incomplete elementary education, living as a spouse in traditional married couple families, or as a child in female-headed families. Psychopathology did not influence refusal.
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PMID:Psychopathology and attrition in the Baltimore ECA 15-year follow-up 1981-1996. 1018 15

This is a review on the recent results of research on sigma-receptor antagonists. NE-100, a selective sigma1-receptor antagonist, shows improvement of abnormal behaviors and cognitive dysfunction induced by phencyclidine (PCP). However, NE-100 does not inhibit dopamine agonist-induced behaviors nor induces catalepsy. The mode of action of NE-100 is estimated to be the indirect modulation of the NMDA/PCP-receptor ion channel complex and the modulation of dopamine release from the dopaminergic nerve terminals. The recently reported MS-355/MS-377, which is also a selective sigma1-receptor antagonist, has a similar pharmacological profiles as NE-100, but in addition, MS-355/MS-377 inhibits methamphetamine-induced formation of reversal tolerance and also inhibits apomorphine-induced climbing behavior like dopamine D2-receptor antagonists. The report on clinical trial targeting schizophrenia shows results on rimcazole, remoxipride, BMY 14802, panamesine (EMD 57445) and SL 82.0715. Rimcazole was effective in the open study, but the double blind trial was discontinued due to seizure induction. Remoxipride showed efficacy different from those of dopamine D2-receptor antagonists (less extrapyramidal adverse effects), but the trial was discontinued due to occurrence of aplastic anemia. Panamesine and SL 82.0714 showed favorable efficacy in the open studies, but BMY 14802 showed no efficacy in clinical trials.
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PMID:[Atypical antipsychotic profiles of sigma receptor ligands]. 1056 61

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine have been known to cause schizophrenia-like psychosis (positive symptoms, negative symptoms, cognitive dysfunction) in humans. A dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia. In this review, the glutamate hypothesis of schizophrenia, especially the mechanism of neurotoxicity of NMDA receptor antagonist in the posterior cingulate cortex and retrosplenial cortex of the brain, is summarized. Furthermore, the roles of the posterior cingulate cortex and the retrosplenial cortex in the pathophysiology of schizophrenia and Alzheimer's disease are also discussed. Moreover, the glycine site of the NMDA receptor, metabotropic glutamate receptor, AMPA receptor, and antioxidant glutathione as novel potential targets for the treatment of schizophrenia are discussed.
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PMID:[Glutamate hypothesis of schizophrenia and targets for new antipsychotic drugs]. 1191 7


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