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)

The non-competitive NMDA antagonist ketamine, given to schizophrenic individuals in subanesthetic doses, produced a short-lived, discrete activation of their psychotic symptoms, which had striking similarities to symptoms of their usual psychotic episodes. To further study this psychotomimetic property of ketamine, we administered 0.3 mg kg-1 of the drug to schizophrenic individuals during a [15O] water cerebral blood flow study. Regional cerebral blood flow (rCBF) was measured using H2(15)O and positron emission tomography (PET) before and after ketamine administration to identify regions of flow change, rCBF was increased in anterior cingulate cortex and was reduced in the hippocampus and primary visual cortex (lingual and fusiform gyri). These data encourage further consideration of altered glutamatergic transmission in schizophrenic and PCP-induced psychoses.
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PMID:Ketamine activates psychosis and alters limbic blood flow in schizophrenia. 761 73

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, MK-801, and phencyclidine (PCP), induce the HSP70 heat shock or stress gene in pyramidal neurons in rat posterior cingulate and retrosplenial cortex. PCP also induces HSP70 in many other pyramidal neurons in brain including neocortex, insular cortex, piriform cortex, hippocampus, and basal nuclei of the amygdala. Several neurotransmitter antagonists, including haloperidol, clozapine, SCH-22390, diazepam, and muscimol, inhibited induction of HSP70 produced by PCP. Baclofen had no effect. Nifedipine blocked induction of HSP70 by PCP in cingulate, neocortex, and insular cortex but only partially blocked HSP70 in piriform cortex and amygdala. These data suggest that phencyclidine injures pyramidal neurons via dopamine D1, D2, D4, sigma, and other receptors. Gamma-aminobutyric acid (GABA) agonists ameliorate the injury. A model is proposed whereby NMDA receptor blockade on GABA neurons decreases inhibitory inputs onto cortical pyramidal neurons and makes them more vulnerable to injury from a variety of excitatory inputs. It is possible that psychosis produced by PCP and other NMDA antagonists correlates with overactivity and eventual injury to cingulate pyramidal neurons.
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PMID:Neuronal injury produced by NMDA antagonists can be detected using heat shock proteins and can be blocked with antipsychotics. 777 Jun 20

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez-like circuit.
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PMID:The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. 779 58

To elucidate the biological activity of natural metabolites of phencyclidine (PCP), we examined the behavioral effects of a major metabolite, the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol [(trans)PPC], in mice, (Trans)PPC caused dose-related increase in locomotor activity and rearing in mice when injected intraperitoneally at the doses ranging from 10 to 30 mg/kg. (Trans)PPC at any dose tested failed to produce swaying and falling. On the other hand, PCP at the doses ranging from 1 to 10 mg/kg caused swaying and falling as well as hyperlocomotion in a dose-related manner. These indicate that unlike PCP, hyperlocomotion and rearing may be the predominant behavioral responses to (trans)PPC in the 10-30 mg/kg dose range. Furthermore, it is feasible to surmise that not only PCP but also its major metabolite (trans)PPC is involved in psychotic reactions produced by PCP.
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PMID:Behavioral effects of phencyclidine and its major metabolite, (trans)4-phenyl-4-(1-piperidinyl)cyclohexanol, in mice. 788 Apr 57

Phencyclidine (PCP; angel dust) is a drug of abuse known to produce a behavioral state in humans resembling schizophrenia/psychosis. PCP is a noncompetitive NMDA receptor antagonist and produces a variety of behaviors in rats including circling. The behavioral effects of other noncompetitive NMDA receptor antagonists such as (+)-MK-801 are still being elucidated. Here, adult female rats were dosed with PCP (10 mg/kg, IP), or (+)-MK-801 (0.1 mg/kg, IP) and circling preference was recorded for 2 h before sacrifice to determine monoamine levels by HPLC/EC. Animals injected with PCP or (+)-MK-801 showed a preference to turn to the left (65% and 72%, respectively). PCP and (+)-MK-801 also produced a significant increase of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in whole striatum on both sides of the brain. Further dissection of the striatum into medioventral and dorsolateral regions revealed that HVA was increased bilaterally except in globus pallidus where we found significant increases in dopamine (DA), DOPAC, and HVA only on the left side after PCP and (+)-MK-801 administration. These data suggest that PCP and (+)-MK-801 produce a greater preference to turn left than right, a finding similar to that found in human psychosis. Furthermore, it is possible that this preference to turn toward the left hemispace is due to an asymmetry in dopamine function found in the globus pallidus after administration of PCP and similar drugs.
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PMID:Phencyclidine and (+)-MK-801-induced circling preference: correlation with monoamine levels in striatum of the rat brain. 796 37

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

Phencyclidine (PCP), a psychotomimetic drug of abuse, produces mental changes and manifestations in humans which are reminiscent of schizophrenia, though the mechanism of these actions remains unknown. We report here a biphasic time course of PCP action on regional cerebral glucose metabolism extending over 48 h. A single dose of PCP (8.6 mg/kg) produces an initial increase in glucose metabolism (at 3 h) and a later decrease in glucose metabolism (at 24 h) without a return to baseline until 48 h. A single lower dose of PCP (0.86 mg/kg), a dose which is considered selective for action at the NMDA-PCP receptor, produces no early metabolic change (at 3 h), but replicates the regional hypometabolism albeit less intense at 24 h. The delayed cerebral hypometabolism does not appear to be related to PCP-induced intracellular vacuolization, seen in the retrosplenial cortex. These metabolic changes may be associated with the psychotomimetic effects of PCP and thus may be relevant to psychosis in humans.
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PMID:Delayed regional metabolic actions of phencyclidine. 822 27

Patterns of neural degeneration were compared following continuous administration of four drugs of addiction, each of which induces model psychoses in chronic addicts. D-amphetamine (D-Amph), cocaine (Coc), or phencyclidine (PCP) were administered continuously over a 5-day period. Both D-Amph and Coc induced pronounced degeneration in fasciculus retroflexus, but only D-Amph further induced substantial degeneration in striatum. Continuous PCP produced entirely different degeneration largely confined to the posterior entorhinal cortex, ventral dentate gyrus, and cingulate cortex. Methamphetamine (Meth) administered in the very high dose but less prolonged drug regimen often employed in studies of dopamine toxicity induced pronounced degeneration in striatum, but widespread degeneration in many other regions as well. These results indicate that drugs of abuse with psychotomimetic properties induce distinctively different patterns of neural degeneration, a finding with implications for theories of addiction and psychosis. They predict two different anatomical loci for alterations in psychosis: fasciculus retroflexus and ventral parahippocampus and hippocampus.
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PMID:Dissimilar patterns of degeneration in brain following four different addictive stimulants. 828 Aug 52

Drugs of abuse, such as phencyclidine (PCP), methamphetamine (METH), and cocaine (COC) are known to affect several behaviors in rats, such as motor activity, stereotypy, and circling. In this study, we evaluated whether these drugs produce circling preferences in the presence or absence of unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the caudate nucleus. Adult male CD rats were lesioned with 10 micrograms 6-OHDA/site. Animals were dosed with PCP (15 mg/kg, ip) its congener (+) MK-801 (0.15 mg/kp, ip), METH (2 mg/kg, ip) COC (60 mg/kp, ip), or apomorphine (0.2 mg/kg, ip). Circling preference was recorded in control and lesioned rats for 2 h before animals were sacrificed to determined monoamine levels by HPLC/EC. In control animals, administration of these drugs produced 60-70% left circling. In lesioned animals, these drugs produced 78-90% ipsilateral (toward the lesion) circling, except apomorphine, which produced 60-80% contralateral (away from the lesion) circling. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly decreased ipsilaterally in lesioned caudate nucleus (CN) and substantia nigra (SN). However, no significant changes were observed in nucleus accumbens (NA) and olfactory tubercles (OT). These data demonstrate that drugs of abuse like PCP, its congener (+) MK-801, METH, and COC produce a greater preference to turn toward the left than the right, a finding similar to that found in human psychosis. Since 6-OHDA lesions enhanced the circling bias and depleted DA and its metabolites DOPAC and HVA, it also suggests that the dopaminergic system may be involved in the circling behavior.
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PMID:Drug-induced circling preference in rats. Correlation with monoamine levels. 856 58

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


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