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: CAS:77-10-1 (Phencyclidine)
442 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phencyclidine (PCP) induces a psychotic state closely resembling schizophrenia in normal individuals. PCP and related agents induce their unique behavioral effects by blocking neurotransmission mediated at N-methyl-D-aspartate (NMDA)-type glutamate receptors, indicating that dysfunction of NMDA receptor-mediated neurotransmission may play a crucial role in the pathophysiology of schizophrenia. NMDA receptors are activated by the amino acids glutamate and glycine, working at independent binding sites. Glutamate cannot be administered exogenously because of excitotoxicity. In contrast, glycine administered exogenously may potentiate NMDA receptor-mediated neurotransmission in vivo following peripheral administration. In rodents, glycine is effective in elevating brain glycine levels and reversing PCP-induced hyperactivity at doses of 0.8 g/kg and above. Three studies have now been completed utilizing moderate to high (0.4-0.8 g/kg/day) doses of glycine, added to neuroleptics, for the treatment of schizophrenia. Across studies, 15 to 30 percent improvement in negative symptoms was observed with no corresponding worsening of positive symptoms. Although preliminary, these studies indicate that dietary supplementation with glycine or treatment with other glycinergic agents may be effective in the treatment of schizophrenia.
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PMID:Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. 899 96

Phencyclidine and other antagonists of the N-methyl-D-aspartate subtype of glutamate receptor cause psychosis in humans. In low doses these agents induce a reversible neurotoxic reaction in the rat brain that is limited to the retrosplenial granular cortex. Some investigators have reported that phencyclidine at higher doses or by more prolonged treatment causes a more disseminated pattern of damage. However, it has not been clearly demonstrated whether the disseminated damage is reversible or irreversible and whether it is consistently reproducible, nor is it known how many and which neurons are at risk. In the present study we addressed these questions using several histological approaches (plastic-embedded thin sections for light microscopy and ultrathin plastic sections for electron microscopy, paraffin-embedded haematoxylin and eosin sections, 72 kDa heat shock protein immunocytochemistry and de Olmos silver impregnation) to study the lesions induced in rat brain by phencyclidine (alone or when augmented with pilocarpine). We found that phencyclidine can kill a relatively large number of neurons distributed over many cerebrocortical and limbic brain regions, but the multifocal pattern of damage occurred in only a small percentage of treated rats. The addition of a low dose of pilocarpine to phencyclidine caused the widespread pattern of damage to manifest on a much more consistent basis. Available evidence suggests that disinhibition of multiple converging excitatory pathways is the mechanism by which phencyclidine triggers widespread neuronal degeneration; however, the specific combination of excitatory inputs that contributes to the pathological process may differ from region to region.
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PMID:Multifocal brain damage induced by phencyclidine is augmented by pilocarpine. 910 35

Phencyclidine and related compounds such as MK-801 produce psychotic symptoms, which closely resemble schizophrenia. MK-801 causes lesions in different corticolimbic regions including the medial entorhinal cortex (mEC). Using electrophysiological recordings in brain slices we tested whether several hours of systemic administration of MK-801 affect stimulus-induced field potentials (FPs) in the mEC. Stimulus-induced FPs were selectively reduced in layer III, but not in layers II and V of the mEC. In contrast, MK-801 applied acutely over the bath in low concentration had no significant effect on evoked FPs. Since the principal cells of layer III project directly to area CA1 and the subiculum, the selective effects of MK-801 may have implications for the transfer of information to the hippocampus.
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PMID:Systemic administration of the phencyclidine compound MK-801 affects stimulus-induced field potentials selectively in layer III of rat medial entorhinal cortex. 912 8

1. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D4 and 5-hydroxytryptamine (5-HT)2A receptor antagonist, was examined in rats. 2. Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED50 3.7 mg kg-1), haloperidol (ED50 0.1 mg kg-1) and chlorpromazine (ED50 0.9 mg kg-1), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg-1, did not exceed 50%. 3. Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg-1, i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED50 0.4 mg kg-1, i.p., and 0.3 mg kg-1, p.o., respectively), clozapine (ED50 0.3 mg kg-1, i.p. and 0.8 mg kg-1, p.o., respectively), haloperidol (ED50 0.02 mg kg-1, i.p. and 0.1 mg kg-1, p.o., respectively), chlorpromazine (ED50 0.3 mg kg-1, i.p. and 3.3 mg kg-1, p.o., respectively). In contrast, the MAP (3 mg kg-1, i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not affected by NRA0045 or clozapine, at the highest dose given (30 mg kg-1, i.p.). Haloperidol (ED50 0.3 mg kg-1, i.p.) and chlorpromazine (ED50 4.8 mg kg-1, i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4. Extracellular single-unit recording studies demonstrated that MAP (1 mg kg-1, i.v.) decreased the firing rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg-1, i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg-1 (i.v.). Clozapine completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg-1, i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg-1, i.v.). Haloperidol completely reversed the inhibitory effects of MAP on A10 (ED50 0.03 mg kg-1, i.v.) and on A9 dopamine neurones (0.02 mg kg-1, i.v.). NRA0045, like clozapine, was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5. Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg-1, s.c.) was reversed significantly by NRA0045 (3 mg kg-1, i.p.), clozapine (3 mg kg-1, i.p.) and haloperidol (0.3 mg kg-1, i.p.). 6. Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03-0.3 mg kg-1, i.p.) and clozapine (0.1-1 mg kg-1, i.p.) significantly and dose-dependently shortened the PCP(1.25 mg kg-1, i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (0.01-0.1 mg kg-1, i.p.) did not significantly alter swimming latency. 7. These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.
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PMID:The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats. 917 95

Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia. In preclinical studies, PCP has been shown to induce its unique behavioral effects by blocking excitatory neurotransmission mediated at the N-methyl-D-aspartate (NMDA) receptors, suggesting that agents which potentiate NMDA receptor-mediated neurotransmission might have clinically beneficial effects. The present study demonstrates that the NMDA co-agonist glycine inhibits rodent hyperactivity induced by PCP, but not amphetamine. Glycyldodecylamide, a compound that blocks neuronal glycine uptake and which may therefore increase intrasynaptic glycine levels, inhibits PCP-induced hyperactivity more potently than glycine. These results complement recent clinical studies with glycine and suggest that glycine-uptake inhibitors, as well as glycine, may be beneficial in the treatment of PCP-induced psychosis and schizophrenia.
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PMID:Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycyldodecylamide. 927 87

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.
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PMID:Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity. 940 19

Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic psychosis. In animal models of schizophrenia, PCP induces locomotor hyperactivity, stereotyped behaviour and social isolation, and the purpose of the present study was to describe the ability of dopamine agonists and antagonists to mimic or interact with these PCP-induced behaviours in rats. The compounds were administered daily for 3 days in combination with vehicle or 2.0 mg/kg PCP and the rats were tested in the social interaction test on the last day of drug administration. The study showed that D1-agonists with relative differences in efficacy at the DA-stimulated adenylate cyclase had limited effects on the PCP-induced behaviours, whereas the D1-antagonist SCH 23391 could alleviate the PCP-induce social isolation following daily treatment for 3 days. However, following long-term treatment for 21 days, the rats develop tolerance to this effect. These data thus suggested that the D1-receptor system only had a modulatory effect on PCP. In contrast, the D2-receptor family may be more directly involved, because the D2/D3/D4-agonist quinpirole could mimic and potentiate the PCP-induced deficits in social behaviour, and the D2/D3-antagonist (-)sulpiride could alleviate the PCP-induced stereotyped behaviour and social isolation. However, a D4-antagonist did not affect the behaviour of vehicle- and PCP-treated rats, suggesting that this system plays a less direct role in the behavioural effects of PCP. In general, however, the effects of SCH 23391, quinpirole and (-)sulpiride on the PCP-induced behaviours were mirrored in the vehicle-treated control groups and it is therefore possible that non-specific effects may have been important.
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PMID:Effects of dopamine agonists and antagonists on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test. 949 24

Phencyclidine, a non-competitive N-methyl-D-aspartate receptor antagonist and indirect dopamine agonist, has neuroprotective properties. Phencyclidine, however, can also exert toxic effects and causes degeneration of neurons in the retrosplenial cortex. In this paper we demonstrate that acute administration of a high dose of phencyclidine to rats, (80 mg/kg), also causes death of a subpopulation of striatal neurons. The dying cells exhibited many of the morphological and biochemical features of cells undergoing apoptosis as revealed by a silver methenamine stain, propidium iodide fluorescence histochemistry and a TUNEL procedure. The majority of the dying cells tended to be clustered within the dorsomedial aspect of the striatum. The type of striatal cell undergoing apoptosis was determined by stereotaxically injecting a colloidal gold retrograde anatomical tracer into the major areas of striatal termination prior to the administration of phencyclidine. This procedure demonstrated that phencyclidine induced striatal apoptosis is almost exclusively limited to striatopallidal neurons. A similar series of experiments was conducted to determine whether the synthetic corticosteroid, dexamethasone, also induces apoptosis of striatal neurons. Corticosteroids are known to be toxic to hippocampal neurons and interact with striatal dopamine transmission. Acute administration of dexamethasone, (20 mg/kg), induced apoptosis of a subpopulation of striatal cells. As was the case with phencyclidine, most of the dexamethasone-induced apoptotic striatal cells were striatopallidal neurons located within the dorsomedial striatum. The pathology during the early stages of Huntington's disease is restricted to an equivalent subpopulation of striatal neurons. Many Huntington's patients are extremely psychotic during this stage in the progression of the disease. Psychosis is also associated with the acute administration of both phencyclidine and dexamethasone to humans. We accordingly speculate that the selective loss of striatopallidal neurons in the dorsomedial striatum may represent the neural substrate of many forms of psychosis.
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PMID:Phencyclidine and corticosteroids induce apoptosis of a subpopulation of striatal neurons: a neural substrate for psychosis? 953 19

Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. In the social interaction test PCP induces stereotyped behaviour and social isolation in rats, and these behaviours can be inhibited by antipsychotic drugs. In order to further evaluate the predictive validity of this model of schizophrenia the anxiolytic diazepam (0.02-17.5 micromol/kg; 0.005-5.0 mg/kg), the antidepressant citalopram (0.62-19.8 micromol/kg; 0.3-4.0 mg/kg), the opioid agonist methadone (0.36-5.8 micromol/kg; 0.13-2.0 mg/kg) and the opioid antagonist naloxone (0.34-22.0 micromol/kg; 0.13-8.0 mg/kg) were tested as examples of drugs without antipsychotic activity. The experiments demonstrated that these compounds did not specifically inhibit the behavioural effects of PCP. So far only antipsychotic drugs have been able to specifically inhibit the PCP-induced behaviours.
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PMID:Effects of diazepam, citalopram, methadone and naloxone on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test. 988 22

Phencyclidine induces a model psychosis which can persist for prolonged periods and presents a strong drug model of schizophrenia. When given continuously for several days to rats, phencyclidine and other N-methyl-D-aspartate (NMDA) antagonists induce neural degeneration in a variety of limbic structures, including retrosplenial cortex, hippocampus, septohippocampal projections, and piriform cortex. In an attempt to further clarify the mechanisms underlying these degeneration patterns, autoradiographic studies using a variety of receptor ligands were conducted in animals 21 days after an identical dosage of the continuous phencyclidine administration employed in the previous degeneration studies. The results indicated enduring alterations in a number of receptors: these included decreased piperidyl-3,4-3H(N)-TCP (TCP), flunitrazepam, and mazindol binding in many of the limbic regions in which degeneration has been reported previously. Quinuclidinyl benzilate and (AMPA) binding were decreased in anterior cingulate and piriform cortex, and in accumbens and striatum. Piperidyl-3,4-3H(N)-TCP binding was decreased in most hippocampal regions. Many of these long-term alterations would not have been predicted by prior studies of the neurotoxic effects of continuous phencyclidine, and these results do not suggest a unitary source for the neurotoxicity. Whereas retrosplenial cortex, the structure which degenerates earliest, showed minimal alterations, some of the most consistent, long term alterations were in structures which evidence no immediate signs of neural degeneration, such as anterior cingulate cortex and caudate nucleus. In these structures, some of the receptor changes appeared to develop gradually (they were not present immediately after cessation of drug administration), and thus were perhaps due to changed input from regions evidencing neurotoxicity. Some of these findings, particularly in anterior cingulate, may have implications for models of schizophrenia.
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PMID:Long-term changes in brain following continuous phencyclidine administration: an autoradiographic study using flunitrazepam, ketanserin, mazindol, quinuclidinyl benzilate, piperidyl-3,4-3H(N)-TCP, and AMPA receptor ligands. 997 84


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