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)

Increased release of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) from slices of striatum of DBA/2J mouse in response to administration of phencyclidine (PCP) in vitro has been observed to be transient, despite continued exposure to PCP. To determine whether this transient response was a result of depletion of releasable pools, toxicity or an adaptive response (desensitization), the recovery of the response to PCP was evaluated. Slices in the control condition were exposed to PCP (300 microM) during test-exposure only. Slices in the PCP pre-exposure condition, were exposed first to PCP (30 microM; pre-exposure) and subsequently to PCP (300 microM; test-exposure). During a washout period (0, 30, 60 or 120 min) between exposures to PCP, the slices were superfused in the absence of PCP. Pre-exposure to PCP diminished the subsequent response to test-exposure to PCP (49 and 37% of control for DA and DOPAC, respectively) after 0 min washout. Overflow of DA evoked by PCP returned towards control values but remained decreased (66% of control) after up to 120 min washout. However, overflow of DOPAC did not return to control values after 60 min washout. Thus, the diminished dopaminergic response, resulting from continued exposure to PCP was not due to depletion of the releasable pool or cytotoxicity but rather to a dynamic adaptive response of the dopaminergic neuron to PCP.
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PMID:Phencyclidine-induced desensitization of striatal dopamine release. 143 85

A mouse model of P-450 phencyclidine 3-cyclohydroxylase (P-450 PCP 3-cyclohydroxylase) genetic polymorphism is described. Up to a 3-fold difference was observed in the constitutive liver microsomal activity of P-450 PCP 3-cyclohydroxylase between "slow" (A/J and DBA/2J) and "rapid" (C57BL/6J and BALB/CJ) phencyclidine (PCP) metabolizers. The segregation of slow and rapid hydroxylator phenotypes between 17 recombinant inbred mouse strains derived from A/J and C57BL/2J mice suggests control of the activity by a single gene located on the X-chromosome or, less likely, on chromosome 17. A liver deficiency of P-450 PCP 3-cyclohydroxylase was observed in the New Zealand rabbit and Wistar rat, as well as in some human subjects. Any relationship of P-450 PCP 3-cyclohydroxylase polymorphism to other well characterized P-450 polymorphisms in mice (aryl hydrocarbon hydroxylase and coumarin hydroxylase) was excluded on the basis of differences in inducibility and activity distribution among the inbred mouse strains. Lack of relationship to the P-450 debrisoquine hydroxylase was confirmed by direct comparison of both activities in the same mouse and human liver microsomes. The pharmacological consequence of the observed polymorphism in mice appears to be that the rapid PCP metabolizers are more resistant to the effects of PCP compared to the slow metabolizers as based upon its ED50 and duration of action in A/J and C57BL/6J mice. The relevance of this data to humans remains to be determined, but clearly the latter show marked differences in PCP 3-cyclohydroxylase activity, which separate into low, intermediate, and high groups.
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PMID:Genetic polymorphism of cytochrome P-450-dependent phencyclidine hydroxylation in mice. Comparison of phencyclidine hydroxylation in humans. 167 21

Non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor have been evaluated as anticonvulsants against sound-induced seizures in DBA/2 mice. The ED50 values for protection against sound-induced clonic seizures 15 min following the intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration are: MK-801, ED50 = 0.5 nmol (i.c.v.); 0.14 mumol/kg (i.p.); phencyclidine, ED50 = 14 nmol (i.c.v.); 1.9 mumol/kg (i.p.); dextrorphan, ED50 = 35 nmol (i.c.v.); 18.5 mumol/kg (i.p.); tiletamine, ED50 = 40 nmol (i.c.v.); 5.6 mumol/kg (i.p.); SKF-10047, ED50 = 50 nmol (i.c.v.); 23.5 mumol/kg (i.p.); dextromethorphan, ED50 = 70 nmol (i.c.v.); 28.0 mumol/kg (i.p.); ketamine, ED50 = 110 nmol (i.c.v.); 15.5 mumol/kg (i.p.). The anticonvulsant effects of ketamine and tiletamine are of short duration (10-30 min), whereas the anticonvulsant effects of MK-801 and dextromethorphan last for 45 min or longer. The effects of phencyclidine, SKF-10047 and dextrorphan are of intermediate duration. Mild to moderate behavioural excitation is associated with the anticonvulsant activity of all the non-competitive NMDA antagonists. For MK-801, phencyclidine, dextrorphan, SKF-10047 and ketamine there is a close correlation between their relative anticonvulsant potencies and their potencies for displacing [3H]MK-801. The anticonvulsant effect is likely to be primarily mediated via NMDA antagonism at the PCP/MK-801 site.
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PMID:Non-competitive N-methyl-D-aspartate antagonists protect against sound-induced seizures in DBA/2 mice. 267 64

Previous studies have demonstrated that the humoral immune response in mice as measured by the splenic IgM response to sheep erythrocytes (SRBC) is highly sensitive to suppression by technical grade (86%) pentachlorophenol (T-PCP) whereas analytical grade (greater than 99%) PCP is not immunosuppressive. In the present studies, we have examined several contaminant fractions and purified isomers from T-PCP for their humoral immunosuppressive effect. C57BL/6 mice were treated with a single oral dose of the various contaminants 2 days prior to SRBC challenge and the peak splenic IgM antibody response was measured 5 days later. Under these exposure conditions, T-PCP produced a dose-related suppression of the antibody response whereas analytical grade PCP was without effect. The dose of T-PCP producing 50% immunosuppression relative to the vehicle-treated control (ID50) was 83 mg/kg. Results from studies using contaminant fractions extracted from T-PCP indicated that a chlorinated dioxin/furan fraction was significantly immunosuppressive, whereas a chlorinated phenoxyphenol fraction and a chlorinated diphenyl ether fraction were without effect when administered at dose levels expected to occur in the ID50 dose of T-PCP. Several purified phenoxyphenol isomers representing the major pre- and isopredioxins in T-PCP were also not immunosuppressive, nor was octachlorodibenzo-p-dioxin. The 1,2,3,4,6,7,8-hexachlorodioxin (HxCDD), 1,2,3,4,6,7,8-heptachlorodioxin (HpCDD), and 1,2,3,4,6,7,8-heptachlorofuran (HpCDF) isomers were all significantly immunosuppressive. The single, oral ID50s were 7.1, 85 and 208 micrograms/kg for HxCDD, HpCDD and HpCDF, respectively. Coadministration of HxCDD and HpCDD produced an additive immunosuppressive effect suggesting that the toxic dioxin and furan isomers present in T-PCP function in concert to produce the degree of immune suppression observed following T-PCP exposure. When analytical grade PCP was coadministered with HpCDD, the degree of immune suppression was equivalent to that produced by HpCDD alone, indicating no significant influence of PCP on dioxin-induced immunosuppression. The enhanced susceptibility of Ah-responsive C57BL/6 mice to T-PCP induced immune suppression as compared to Ah-nonresponsive DBA/2 mice and the correlation of immune suppression with P1-450 associated monoxygenase induction provided further evidence for the role of the toxic Ah-interactive dioxin and furan contaminants in T-PCP as the mediators of T-PCP immunotoxicity.
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PMID:Humoral immunotoxicity of polychlorinated diphenyl ethers, phenoxyphenols, dioxins and furans present as contaminants of technical grade pentachlorophenol. 404 36

The anticonvulsant effects of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), phencyclidine (PCP) and diazepam against audiogenic seizures in DBA/2 mice and against seizures induced by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in NMRI mice were compared. Motor impairment was assessed in a rotarod apparatus in DBA/2 as well as NMRI mice. At 30 min after i.p. administration, NBQX was as effective as PCP and diazepam in protecting against audiogenic seizures and had a therapeutic ratio slightly higher than diazepam's and 7-fold higher than PCP's. Whereas diazepam was fully effective, NBQX and PCP were both ineffective against seizures induced by DMCM 30 min after i.p. administration. The anticonvulsant potential and motor-impairing effects of NBQX were evaluated further by the i.p. and the i.v. routes at different time points after administration. At all pretreatment intervals, NBQX protected against audiogenic seizures more potently than it produced motor impairment. NBQX administered i.p. protected against DMCM-induced seizures when given 15 min but not 5 min before testing, whereas after i.v. administration NBQX produced anticonvulsant and motor-impairing effects in the same dose range. NBQX only slightly and non-dose-dependently attenuated the discriminative effects of pentylenetetrazole in rats, showing a limited anxiolytic potential. NBQX produced no PCP-like or morphine-like discriminative effects in rats, suggesting lack of PCP or opiate-like subjective effects. These data demonstrate that NBQX has anticonvulsant effects, has limited anxiolytic effects, and does not produce subjective effects of PCP or opiate type.
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PMID:Anticonvulsant, anxiolytic and discriminative effects of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX). 756 77

The role of phencyclidine (PCP) in the control of the spike-and-wave spindling episodes (S&W) which can be spontaneously recorded in the electrocorticogram (ECoG) of DBA/2J mice was investigated. PCP (0.1-0.5-1.0-5.0 mg/kg/i.p.) dose dependently reduced both S&W number and duration of DBA/2J mice. PCP reduction is significant 30-60 min after drug administration and lasts for the whole duration of the recording period (240 min). These results suggest that PCP may play an important regulatory role on brain excitability.
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PMID:Phencyclidine reduces inherited neocortical spindling in DBA/2J mice. 815 22

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

There is in vitro evidence that some of the effects of abused volatile solvents may be produced by actions at the NMDA receptor. In addition, some solvents produce phencyclidine-like discriminative stimulus effects. The major goal of the present study was to further compare abused solvents to NMDA antagonists by testing them in two strains of mice trained to discriminate 0.17 mg/kg of the very selective uncompetitive NMDA antagonist, dizocilpine, from saline and contrast those results with several GABA(A)-positive modulators, PCP and ethanol. The results indicated that the discriminative stimulus produced by 0.17 mg/kg dizocilpine was highly specific in both mouse strains. PCP produced 91% dizocilpine-lever responding in C57BL/6J mice, but only 56% dizocilpine-lever responding in DBA/2J mice. Pentobarbital, midazolam and ethanol produced at least some overlap in discriminative stimulus effects with dizocilpine in one or both mouse strains. In contrast, toluene, 1,1,1-trichloroethane (TCE), xylene and methoxyflurane produced saline-appropriate responding almost exclusively. These data indicate that, at least under the specific conditions tested, abused volatile solvents do not have substantial dizocilpine-like discriminative stimulus effects in either C57BL/6J or DBA/2J mice, providing little support that NMDA antagonism plays a central role in the production of this abuse-related effect.
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PMID:Effects of abused inhalants and GABA-positive modulators in dizocilpine discriminating inbred mice. 1550 Dec 97

Schizophrenic patients have deficits in prepulse inhibition (PPI) that may be alleviated by smoking/nicotine. The effect of nicotinic agents on PPI in rodents is equivocal and few studies in mice have been reported. Thus, we assessed nicotine's (0.03-1mg/kg) effect on PPI in five mouse strains with no effects. We next determined if nicotine would reverse a phencyclidine (PCP)-induced deficit of PPI in BALB/cByJ and NMRI mice. BALB/cByJ mice have a low density of [(125)I]alpha-bungaratoxin binding in the hippocampus and poor inhibitory gating of auditory evoked potentials (AEPs), a model related to PPI. At 1mg/kg, nicotine selectively reversed the PCP-induced deficit of PPI in BALB/cByJ mice. The pharmacokinetic profile of nicotine (T(1/2), C(max), T(max) and AUC) was identical in both strains, obviating this as a factor for the strain-dependent effect observed. Moreover, 1mg/kg nicotine inhibited in vivo [(3)H]epibatidine binding with the same time-course in both strains, indicating no difference in brain "kinetics". Since high doses of nicotine were effective in BALB/cByJ mice a role for low-affinity nicotinic receptors, e.g. alpha(7) receptors, is plausible. Clozapine, but not risperidone, also only reversed the PCP deficit of PPI in BALB/cByJ. Clozapine and nicotine also enhance inhibitory gating of AEPs in DBA/2 mice, and clozapine's effect is antagonized by an alpha(7) antagonist. Our data and previous evidence possibly suggest a role for low-affinity nicotinic receptors in the effects of clozapine and nicotine. Furthermore, BALB/cByJ mice may represent a model to test the effects of nicotinic agents acting at low-affinity nicotinic receptors.
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PMID:Nicotine and clozapine selectively reverse a PCP-induced deficit of PPI in BALB/cByJ but not NMRI mice: comparison with risperidone. 1622 35

The phenotype of genetically modified animals is strongly influenced by both the genetic background of the animal as well as environmental factors. We have previously reported the behavioral and neurochemical characterization of PDE10A knockout mice maintained on a DBA1LacJ (PDE10A(DBA)) genetic background. The aim of the present studies was to assess the behavioral and neurochemical phenotype of PDE10A knockout mice on an alternative congenic C57BL/6N (PDE10A(C57)) genetic background. Consistent with our previous results, PDE10A(C57) knockout mice showed a decrease in exploratory locomotor activity and a delay in the acquisition of conditioned avoidance responding. Also consistent with previous studies, the elimination of PDE10A did not alter basal levels of striatal cGMP or cAMP or affect behavior in several other well-characterized behavioral assays. PDE10A(C57) knockout mice showed a blunted response to MK-801, although to a lesser degree than previously observed in the PDE10A(DBA) knockout mice, and no differences were observed following a PCP challenge. PDE10A(C57) knockout mice showed a significant change in striatal dopamine turnover, which was accompanied by an enhanced locomotor response to AMPH, These studies demonstrate that while many of the behavioral effects of the PDE10A gene deletion appear to be independent of genetic background, the impact of the deletion on behavior can vary in magnitude. Furthermore, the effects on the dopaminergic system appear to be background-dependent, with significant effects observed only in knockout mice on the C57BL6N genetic background.
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PMID:Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background. 1806 Dec 15


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