Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. In rats, acute PCP treatment increased locomotor activity and induced stereotyped behaviours consisting of head weaving, turning and backpedalling. PCP had differential regional effects on c-fos expression in rat brain, suggesting different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. To elucidate the role of nitric oxide, an important intracellular messenger, in the mechanism of action of PCP the effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were studied in PCP-treated animals. L-NAME potentiated PCP-induced behaviours and c-fos expression in many brain regions. The greatest increases were observed in the frontal, retrosplenial granular cortex, cerebellum, thalamic and subthalamic nuclei. While PCP alone induced low c-fos expression in the entorhinal cortex, with almost no expression in the rostral part of caudate putamen, animals pretreated with L-NAME showed marked activation in these brain areas. These results strongly indicate the involvement of the nitric oxide system in the mechanism of action of PCP.
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PMID:Effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester on phencyclidine-induced effects in rats. 1109

Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled-unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP.
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PMID:Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats. 1111 8

Phencyclidine (PCP) reduced social behavior (SB) in a dose- and time-dependent fashion. However, no such SB deficit was observed on repeated treatment with methamphetamine for 14 days. The SB deficit produced by treatment with PCP (10 mg/kg/day) for 14 days, which persisted for 28 days after withdrawal, was attenuated by clozapine (10 mg/kg/day) given for 7 days, whereas haloperidol for 7 days had no effect. Clozapine, but not haloperidol, alone at the same treatment dose increased SB in saline-treated mice. These results suggest that the proposed PCP model in mice will provide a tool to test beneficial effects of atypical antipsychotics on social dysfunction in schizophrenia, and contribute to our understanding of the mechanisms by which clozapine improves SB deficit.
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PMID:Clozapine, but not haloperidol, reverses social behavior deficit in mice during withdrawal from chronic phencyclidine treatment. 1120 Oct 68

Disruption of prepulse inhibition (PPI) of acoustic startle in rats has been widely used as an animal model for the sensorimotor gating deficit state usually found in schizophrenia. PPI was reported to be regulated by forebrain circuits, including mesolimbic cortex, nucleus accumbens, ventral pallidum, thalamus, and pedunculopontine tegmentum nucleus. Phencyclidine or dopamine agonists, which causes psychotomimetic symptoms in humans, disrupts PPI in animals. The ED50 value of the drugs to reverse the phencyclidine-induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D2 receptor of each drug (including atypical antipsychotics). In contrast, the ED50 value of the drugs to reverse the apomorphine-induced PPI disruption was significantly correlated with the affinity for the dopamine D2 receptor (including typical antipsychotics). Thus the drug that antagonizes the disruption of PPI caused by PCP or DA agonists would be a candidate for a therapeutic agent for the sensorimotor gating deficit state in schizophrenic patients. Neural mechanisms underlying the disruption of PPI were reviewed.
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PMID:[Disruption of prepulse inhibition of acoustic startle as an animal model for schizophrenia]. 1121 97

Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. The purpose of the present study was to determine whether PCP can induce similar behavioural effects in rats and whether these effects can be alleviated by neuroleptic drug treatment. Rats were tested in the social interaction test, and their behaviour was quantified by an automated video-tracking system and manual scorings of stereotyped behaviour and ataxia. The behavioural effects of different dose- and administration regimes of PCP were initially determined, and it was found that PCP dose-dependently induced stereotyped behaviour and social isolation in the rats. Comparison to clinical studies suggests that these behaviours correspond to certain aspects of the positive and negative symptoms, respectively, of a PCP psychosis in humans. Subsequently, the effects of 3 or 21 days of administration of the antipsychotic drugs haloperidol or clozapine on the behaviour of either vehicle- or PCP-treated rats were determined. Haloperidol did not produce a selective antagonism of PCP, whereas chronic clozapine selectively inhibited the PCP-induced stereotyped behaviour and social isolation. These effects of haloperidol and clozapine suggest that this animal model can determine the effects of neuroleptic drugs on positive and negative symptoms, onset of action, and side-effect profile, including effects on the motor system. Together these data suggest that this may be a possible animal model of the positive and negative symptoms of schizophrenia.
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PMID:Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. 1122 90

Metabotropic glutamate receptors (mGluRs) belong to the class of GTP-binding protein coupled receptors and consist of eight different subtypes. The subtype 2 metabotropic glutamate receptor (mGluR2) gene (GRM2) is one of the possible candidate genes for schizophrenia. Phencyclidine (PCP)-induced increase in glutamate efflux and schizophrenia-like behavioral abnormalities were reduced by pretreatment of the mGluRII agonist LY354740 in rats and its effects are mediated via mGluR2. To evaluate involvement of the mGluR2 gene in the pathogenesis of schizophrenia, we isolated the human mGluR2 gene and determined the transcription initiation site, the entire nucleotide sequence and the chromosomal localization. The hmGluR2 gene spans 13 kb with six exons, including one non-coding exon. The gene was mapped to chromosome 3 p12-p11 by Radiation Hybrid Panel analysis. We screened polymorphisms in the coding exons of the mGluR2 gene, using the SSCP procedure. The thirteen polymorphisms identified included ten missense, one silent mutation and two one-base substitutions in the 5'-untranslated region. We genotyped 213 Japanese schizophrenics and 220 controls to study the association of polymorphisms in the mGluR2 gene with schizophrenia. As we found no statistically significant differences in allele frequencies of each polymorphism, these polymorphisms apparently do not play a major role in schizophrenia.
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PMID:Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia. 1131 21

Phencyclidine (PCP) administration in rodents has been used to model aspects of schizophrenia. One aspect of such treatment has been the enhancement of amphetamine-induced increase of dopamine in the prefrontal cortex and striatum. To further characterize this mechanism rats were treated for 2 weeks with continuous PCP (15 mg/kg per day via Alzet minipump). Rats were implanted with a microdialysis probe into the prefrontal cortex (PFC) or striatum. Amphetamine was administered locally via the dialysis probe during one collection period and changes in extracellular dopamine were monitored. The effect of local administration of the dopamine uptake blocker nomifensine was also measured. Amphetamine (10 microM) and nomifensine (10 microM) increased the level of dopamine in both the PFC and striatum. PCP administration did not alter the response to amphetamine or nomifensine in the PFC, but reduced this response about 2-fold in striatum. To examine effects of continuous PCP administration on dopamine autoreceptor function, release of [3H]dopamine in response to electrical stimulation and in the presence of a dopamine agonist or antagonist was tested in striatal and prefrontal cortical tissue. Autoreceptor responses were similar in control and PCP-treated tissues. We conclude that the brain region-specific enhancement of dopamine release by peripheral amphetamine administration in rats after PCP is not likely mediated by alterations in the dopamine autoreceptors or changes in the dopamine transporter. The selective local responses of amphetamine indicates heterogeneous regional effects of continuous PCP on NMDA receptor function; effects that influence both regional excitatory responses and the overall dynamics of tonic excitatory/inhibitory inputs to the PFC and striatum.
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PMID:Phencyclidine-induced dysregulation of dopamine response to amphetamine in prefrontal cortex and striatum. 1169 27

Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7, 9 and 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X(L) proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy.
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PMID:Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. 1172 Jul 78

Phencyclidine (PCP) is a dangerous drug, and the federal government has placed it on Schedule II of the Controlled Substance Act (see http:// www .mninter.net/-publish/csa2.htm#Schedule%20III). Typically, users smoke PCP, and it is often mixed with parsley, marijuana, or cocaine. Most researchers have conducted experiments on animals rather than on people, and a few have been done on persons diagnosed with schizophrenia, so answers to questions about its addictive potential or development of tolerance are not clear. In healthy volunteers, PCP can induce symptoms that mimic those of schizophrenia, lasting from a few days to more than a week. The neurotransmitter glutamate and N-methyl-D-aspartate (NMDA) appear to play a role in the mechanism by which PCP induces positive and negative schizophrenic symptoms and cognitive defects (D. C. Javitt & S. R. Zukin, 1991; A. Lahti, B. Koffel, D. LaPorte, & C. A. Tamminga, 1995; T. W. Robbins, 1990). Because PCP can induce symptoms that are almost indistinguishable from those associated with schizophrenia, further research may lead to new medications that could be helpful to people who do not respond to neuroleptics that are currently available.
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PMID:Phencyclidine (PCP): a dangerous drug, but useful in schizophrenia research. 1220 80

Phencyclidine (PCP) is a drug of abuse that has rewarding and dysphoric effects in humans. The complex actions of PCP, and PCP withdrawal in particular, on brain reward function remain unclear. The purpose of the present study was to characterize the effects of withdrawal from acute and chronic PCP treatment on brain reward function in rats. A brain stimulation reward procedure was used to evaluate the effects of acute PCP injection (0, 5, or 10 mg/kg) or chronic PCP treatment (0, 10, 15, or 20 mg/kg/day for 14 days delivered via subcutaneous osmotic minipumps) on brain reward function. Withdrawal from acute administration of 5 and 10 mg/kg PCP produced a decrease in brain reward function as indicated by a sustained elevation in brain reward thresholds. When administered chronically, 10, 15, or 20 mg/kg/day PCP induced a progressive dose-dependent potentiation of brain stimulation reward, while cessation of the treatment resulted in significant elevations in reward thresholds reflecting diminished reward. Specifically, withdrawal from 15 or 20 mg/kg/day PCP induced a depression in brain reward function that lasted for the entire month of observation. These results indicate that prolonged continuous administration of high PCP doses facilitates brain stimulation reward, while withdrawal from acute high PCP doses or chronic PCP treatment results in a protracted depression of brain reward function that may be analogous to the dysphoric and anhedonic symptoms observed in PCP dependence, depression, and schizophrenia.
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PMID:Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function. 1270 Jul


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