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)

Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their functional importance in mental activity is considerable. Therefore, the involvement of this neurotransmitter in the pathology of schizophrenia is being studied. Biochemical evidence has suggested that glutamatergic transmission may be regionally reduced in schizophrenia, although this evidence has never been completely consistent nor fully replicable. More striking has been the behavioral effects in humans of the antiglutamatergic drugs phencyclidine (PCP) and its congener ketamine. By historical report, PCP produces a 'schizophrenia-like' psychosis in normal humans and aggravates the psychosis in schizophrenics. More recently, ketamine has been shown to produce a mild psychotomimetic effect in normal volunteers, which has some schizophrenia-like features. We have studied the effects of ketamine in schizophrenic patients. Here, ketamine intensified each patient's specific underlying psychosis, an effect not blocked by haloperidol. Moreover, ketamine selectively increased cerebral blood flow (CBF) in the anterior cingulate cortex and reduced CBF in hippocampus and lingual gyrus. These data may be pertinent to the subject's psychosis exacerbation, especially because both cingulate and hippocampus have been previously implicated in schizophrenic psychosis. In addition, ketamine produced a distinctive dynamic time-course of regional CBF changes in different anatomic regions, with immediate (5-10 min) changes in cingulate, but somewhat more delayed changes (20-40 min) in the thalamus and cerebellum. Our immediate early gene (IEG) time-course data with c-fos and zif268 in rats following PCP suggest that a single dose of this antiglutamatergic compound can have an effect in some brain areas which lasts beyond 48 h, an effect which is distinct by IEG and by region. Together, these data suggest that glutamate-mediated neurotransmission has a strong influence in schizophrenia, although the specifics of this involvement have yet to be articulated.
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PMID:Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. 886 63

To date, the ketamine/PCP model of psychosis has been proposed to be one of the best pharmacological models to mimic schizophrenic psychosis in healthy volunteers, since ketamine can induce both positive and negative symptoms of schizophrenia. At subanesthetic doses, ketamine has been reported to primarily block N-methyl-D-aspartate (NMDA) receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. Positron emission tomography was used to study ketamine-induced psychotic symptom formation in relation to cerebral metabolic alterations in healthy volunteers. Our study shows that NMDA receptor blockade results in a hyperfrontal metabolic pattern. Increased metabolic activity in the frontomedial and anterior cingulate cortex correlated positively with psychotic symptom formation, in particular with ego pathology. Analysis of correlations between syndrome scores and metabolic rate of glucose (CMRglu) or metabolic gradients (ratios) revealed that each psychopathological syndrome was associated with a number of metabolic alterations in cortical and subcortical brain regions, suggesting that not a single brain region, but distributed neuronal networks are involved in acute psychotic symptom formation.
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PMID:Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). 908 81

Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.
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PMID:Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). 908 82

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