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)

Prepulse inhibition of acoustic or tactile startle (PPI), a form of sensorimotor gating, occurs when a weak prestimulus precedes a startling stimulus and inhibits the startle response. Studies of PPI have revealed that schizophrenic patients exhibit a deficit in this form of sensorimotor gating. In rats, PPI is blocked by dopamine agonists such as apomorphine or quinpirole, effects that are antagonized by haloperidol. Phencyclidine (PCP) has been suggested as a possible model psychotogen and produces a deficit in PPI that is similar to what is observed in schizophrenic patients. Dizocilpine is an anticonvulsant drug that, like PCP, is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA)-induced excitations in brain and also disrupts PPI. In the present study, PPI of acoustic and tactile startle was measured in male Sprague-Dawley rats after injections of 5.0 mg/kg PCP with or without pretreatment with 0.02 or 0.1 mg/kg haloperidol, or with 0.5 mg/kg dizocilpine with or without pretreatment with 0.1 mg/kg haloperidol. The 0.1 mg/kg dose of haloperidol blocks the effects of apomorphine or quinpirole on PPI in rats. Startle was elicited by noise bursts at 105 or 120 dB or by air-puffs (tactile) and was inhibited by 75 or 85 dB prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. Both NMDA antagonists significantly reduced the amount of PPI induced by the 75 dB prestimulus, independently of the level of startle responses elicited by the startle stimuli. Haloperidol did not block the disruption of PPI induced by either PCP or dizocilpine. In addition, PCP was unable to block PPI when the 85 rather than the 75 dB prepulse was used to inhibit either acoustic or tactile startle. These results confirm that putative NMDA antagonists inhibit sensorimotor gating in rats and suggest that these effects are not mediated by the activation of central dopamine systems.
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PMID:Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle. 183 31

Recently, the presence of two high affinity binding sites for phencyclidine were described in guinea pig brain, with one site coupled to the glutamate excitatory amino acid receptor, specifically activated by N-methyl-D-aspartate (NMDA) (site 1) and the other site associated with the dopamine (DA) reuptake carrier (site 2). Phencyclidine and its analogs, as well as the benzomorphan opiates, are known to interact with binding sites for phencyclidine. In this study, the equilibrium dissociation constants (Kd) of these compounds for the two binding sites for phencyclidine were determined. Phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analog of PCP, were essentially non-selective between the two sites and also were the two drugs of the group observed to have the highest affinity for site 2. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine [(+)MK801] was the most selective agent for site 1, while none of the drugs tested showed selectivity for site 2. In humans, phencyclidine produces psychotomimetic effects, while (+)MK801 has been reported to produce minimal, if any, psychotomimetic effects, at doses sufficient to reduce seizures. These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2.
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PMID:Specificity of phencyclidine-like drugs and benzomorphan opiates for two high affinity phencyclidine binding sites in guinea pig brain. 196 80

Phencyclidine (PCP) binds with high affinity to two receptors in rat brain--the PCP receptor and the Sigma receptor. Although both receptors are present prenatally, and their number increases postnatally, their rate of increase, compared to the increase in brain protein, is quite different, yielding distinct ontogenic profiles. Thus, PCP receptors are present on prenatal day 2 and show a further 15-fold increase by postnatal day 28. In contrast, Sigma receptors are present at their highest density during the perinatal period, and decline thereafter. The Kd of the PCP receptor for TCP remains constant throughout development, whereas the Kd of the Sigma receptor for (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine decreases 40% postnatally. On postnatal day 6, both PCP and Sigma receptors display a pharmacological profile similar to that observed in adult animals.
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PMID:Ontogeny of PCP and sigma receptors in rat brain. 215 61

Several lines of evidence suggest a tight functional coupling between N-methyl-D-aspartate (NMDA) and phencyclidine (PCP) receptors. The effects of PCP receptor agonists (PCP, dexoxadrol, ketamine and MK-801) and NMDA receptor antagonists, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) and 3-(2-carboxypiperizin-4-yl)-propyl-1-phosphonic acid (CPP), have been examined on the metabolism of dopamine in the mesocortex, with a view of studying the coupling between these two receptor systems. Phencyclidine receptor agonists selectively increased the metabolism of dopamine in the mesocortex without affecting the metabolism of dopamine in the striatum. N-Methyl-D-aspartate and the competitive antagonists of NMDA receptors did not effect the metabolism of dopamine, neither did the sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) and rimcazole. Rimcazole also did not affect the increases in the metabolism of dopamine in the mesocortex, seen after MK-801. These data indicate that dopaminergic neurons in the mesocortex are positively modulated by PCP receptors but tentatively suggest that those recognition sites for PCP are not coupled to NMDA receptors.
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PMID:Selective activation of dopaminergic pathways in the mesocortex by compounds that act at the phencyclidine (PCP) binding site: tentative evidence for PCP recognition sites not coupled to N-methyl-D-aspartate (NMDA) receptors. 215

Phencyclidine (PCP) markedly stimulates the pituitary-adrenal axis in the rat, inducing the release of adrenocorticotropin (ACTH) and corticosterone. However, the site or sites where PCP produces these effects is not known. This study sequentially examined the effects of PCP on the different components of the central nervous system-pituitary-adrenal axis. PCP did not produce corticosterone release in dispersed adrenal cells in vitro, nor did it stimulate the release of corticosterone in hypophysectomized rats, showing that PCP-induced corticosterone release in intact animals is secondary to the release of ACTH from the pituitary. PCP failed to alter either the basal or the corticotropin releasing factor-induced release of ACTH from superfused pituitaries in vitro, indicating that PCP does not act directly at the level of the pituitary. PCP increased plasma levels of ACTH in adrenalectomized rats, demonstrating that PCP does not stimulate the release of ACTH only by blocking glucocorticoid negative feedback mechanisms. PCP stimulated the release of both ACTH and corticosterone when given by injection directly into brain via the lateral cerebral ventricles. These results indicate that PCP activates the pituitary-adrenal axis by acting at a site or sites within the central nervous system, leading to the subsequent release of ACTH from the pituitary.
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PMID:Determination of the loci of action of phencyclidine on the CNS-pituitary-adrenal axis. 216 1

Phencyclidine (PCP) binds with high affinity to the ion channel associated with the NMDA receptor. The binding of the PCP receptor-specific ligand TCP is greatly reduced at temperatures between 2 degrees C and 6 degrees C, at which the plasma membrane is in a rigid state. However, membrane rigidity alone does not appear to cause the reduced TCP binding, since the membrane fluidizing agent A2C did not increase TCP binding at 4 degrees C; instead, it decreased binding at 21 degrees C. This inhibitory effect of A2C on TCP binding was dose dependent and was highly correlated with A2C-induced increases in membrane fluidity. The IC50 of A2C inhibition was 8.9 mM, with a pseudo-Hill coefficient of -0.24. Scatchard analysis demonstrated that this effect was the result of an increase in the apparent KD of [3H]TCP for the PCP receptor, with no effect on the Bmax. These results suggest that the function of the NMDA-PCP receptor complex is impaired by increases in membrane fluidity. These findings may be pharmacologically relevant in understanding the mechanism of action of such agents as general anesthetics and ethanol, which cause increases in plasma membrane fluidity.
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PMID:Effects of membrane fluidity on [3H]TCP binding to PCP receptors. 217 11

A review of police records for the nine-year period from 1974 to 1982 identified 20 men who died following restraint by an upper-body control hold while in the custody of a large, urban police department. Using evidence from autopsy findings and police reports of events immediately preceding death, we concluded that control-hold use was associated with death in 19 of the 20 cases. This investigation points to three factors potentially associated with control hold-related death that deserve further investigation: Phencyclidine (PCP) use, sickle cell trait, and stress-related arrhythmias in the heart. PCP was detected in blood or other tissues from 6 of 17 decedents tested. Intravascular red blood cell sickling was found at autopsy in 4 of 14 black decedents (29%). Four decedents had some indication of cardiovascular abnormalities.
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PMID:Mortality associated with the use of upper-body control holds by police. 227 99

Phencyclidine (PCP) remains a widely used illicit drug, especially among adolescents and young adults. The pharmacologic effects of PCP are similar to those of cocaine; therefore, in this retrospective study 37 PCP-intoxicated parturients were matched for ethnicity, tobacco use, age, gravidity, and degree of prenatal care with 37 cocaine-intoxicated parturients. Infants exposed to PCP in utero, like those exposed to cocaine, had a high incidence of intrauterine growth retardation (32 vs 19%, N.S.), precipitate labor (43 vs 27%, N.S.), symptoms of neonatal drug withdrawal/intoxication, and prolonged neonatal hospitalizations. Moreover, they were more likely to have meconium-stained amniotic fluid (30 vs 19%, p = .05) and less likely to be born prematurely as cocaine-exposed infants. The comparison between the long-term developmental outcome of these groups awaits further study.
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PMID:Perinatal outcome associated with PCP versus cocaine use. 228 31

Phencyclidine (PCP) pharmacokinetics and drug discrimination were examined in pigeons (n = 6 in both groups) after intramuscular doses of 1.48 mg/kg. PCP absorption was rapid with maximum measured plasma concentrations ranging from 559 to 1450 ng/ml at 10-30 min after dosing, which corresponded to the time of maximum PCP stimulus effects in the drug discrimination studies. The terminal elimination half-life was 0.88 hr (harmonic mean). Average values for the volume of distribution and total body clearance were 1.6 l/kg and 18.2 ml/min/kg, respectively. In the behavioral studies, pigeons discriminated PCP-like effects from about 2 min to 2 hr after dosing. An average value for response on the PCP-appropriate key and for PCP concentration at each time point from 2 min to 2 hr was calculated from the individual subject data. Least-squares linear regression analysis of these data showed a highly significant relationship between the ability to discriminate PCP and log PCP concentration (y = 103x - 219, r2 = .810, p less than 0.005). This analysis suggests PCP concentration is a good predictor of behavioral efficacy.
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PMID:Phencyclidine pharmacokinetics and concentration-response relationships in the pigeon. 234 58

Phencyclidine (PCP) sensitivity of rats, whose body weights were maintained at 70% of free-feeding controls, was compared to drug sensitivity of the controls in terms of unconditioned (exploratory) behavior and plasma corticosterone levels. Low doses of PCP HCl [0 (saline vehicle), 0.3 or 0.9 mg/kg, SC] were given to food-deprived rats and to free-feeding controls 15 minutes before measuring unconditioned behavior for 90 minutes; then PCP in brain and corticosterone in plasma were assayed. An additional group (0.43 mg/kg) was established from the reduced-weight rats in order to compare with free-feeding rats given 0.3 mg/kg, the same absolute dose-a circumstance reflecting "street" usage in which doses are not adjusted for body weight differences among users. These low doses of PCP altered exploratory behaviors, but there did not appear to be an interaction between food-deprivational status and drug, with the possible exception of an altered effect of PCP upon habituation in the lighter animals. PCP elevated plasma corticosterone levels over saline controls only in the reduced-weight rats. The drug, possibly reflecting a tranquilizing action of the lowest dose, reduced corticosterone levels in free-feeding controls. Brain levels of drug were directly related to dose, and were elevated in the food-deprived animals 26-30% over those at the same per-weight dose levels in the free-feeding rats, in spite of being given lower absolute amounts of drug. In the 0.43 mg/kg reduced-weight dose group, given the same absolute dose as the 0.3 mg/kg free-feeding group, brain levels were doubled over the latter group, and exploratory behavior was correspondingly different from the free-feeding group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Food deprivation alters behavioral and plasma corticosterone responses to phencyclidine in rats. 237 47


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