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)

Phencyclidine (PCP) administration in rats acutely in high doses or chronically in lower doses causes neurotoxicity characterized by neuronal vacuolization and apoptotic neuronal death, respectively. The purpose of this study was to determine whether drugs that previously had been reported to prevent either type of neurotoxicity were also able to prevent locomotor sensitization following chronic PCP administration. PCP (5 or 20 mg/kg) was administered once a day for 5 days following drug pretreatment. After withdrawal, rats were challenged with 3.2 mg/kg PCP and locomotor activity was assessed. Haloperidol and clozapine significantly attenuated sensitization elicited by PCP (20 mg/kg). The D(1)-like antagonist SCH23390 was much less effective than clozapine, showing a marginal inhibition. Risperidone, a D(2)/serotonin (5-HT(2)) antagonist, also resulted in a marginal attenuation of 15%. Ketanserin, a 5-HT(2) antagonist, had no effect. Atropine retarded sensitization by 35% and (+)-sulpiride caused a 50% reduction. The AMPA/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione, had no effect, but barbital sodium reduced sensitization by 54%. These data suggest that gamma-aminobutyric acid A, D(2), and muscarinic receptors play a major role in the complex pathway underlying sensitization to PCP, whereas D(1), 5-HT(2) and AMPA receptors have little or no relevance in the behavioral sensitization produced by 20 mg/kg PCP. In a model using 5 mg/kg PCP, the effects of sulpiride and SCH23390 replicated those observed with 20 mg/kg PCP and further showed that acute locomotor activation is not a strict requirement for the development of sensitization. These data argue that there is overlap, but nonidentity, between the mechanisms underlying PCP-induced sensitization and neurotoxicity.
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PMID:Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration. 1118 23

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

Nitric oxide synthase (NOS) is thought to migrate improperly during development in the brains of schizophrenic patients. Also it is known that nitric oxide (NO) effects synaptogenesis during development of the CNS. Previously we have shown that neonatal treatment with a NOS inhibitor effects an animal's sensitivity to amphetamine and PCP. In the present study, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine, 10mg/kg, s.c.) daily on post-natal days (PD) three, four and five. L-Nitroarginine (L-NoArg) treated male rats at adulthood (PD56 and older) had a deficit in social interaction (SI) when placed in an environment with another foreign male rat and this deficit was reproducible on a weekly basis for at least five weeks. Haloperidol failed to significantly reverse this deficit before pronounced secondary effects on general behavior were seen at high doses. However, the atypical antipsychotics, clozapine and olanzapine, were able to significantly reverse this deficit at doses which did not effect baseline SI values. In a separate cohort of animals the effect of DOI was investigated, this was done to ascertain if there was a differential sensitivity of serotonergic pathways in this model. There was no difference in the behavioral score elicited from control or NoArg-treated rats. It is suggested that the SI deficits seen here may be more sensitive to atypical antipsychotics rather than haloperidol.
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PMID:Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs. 1189 19

The ability of antipsychotic drugs to affect 5-HT(2A) receptor function has been widely suggested to contribute to their therapeutic properties. We have compared the ability of the antipsychotic drugs clozapine and haloperidol, alone and in combination with chronic phencyclidine (PCP), to modulate 5-HT(2A) receptor binding and mRNA. Acute (i.p. 45 min) and chronic (21-day) clozapine (osmotic minipump (OMP); 20 mg/kg/day) produced widespread decreases in 5-HT(2A) receptor binding (-60%-80%), measured using [(3)H]ketanserin autoradiography. Conversely, 5-HT(2A) mRNA levels, determined using in-situ hybridisation, were modestly increased by chronic clozapine treatment (+10%-30%). Chronic PCP treatment, at a dose (2.58 mg/kg i.p. intermittently for 28 days) that reproduces many of the neurochemical deficits of schizophrenia, decreased 5-HT(2A) receptor binding in the prefrontal cortex (PFC; -16%), consistent with the changes in post-mortem brain tissue from schizophrenic patients. Combined chronic PCP (i.p.) and clozapine (OMP) treatment down-regulated 5-HT(2A) receptor binding in many areas, similar to the effects of clozapine treatment alone and clozapine further enhanced the effects of PCP in the prefrontal cortex. In contrast 5-HT(2A) mRNA was not altered. Haloperidol treatment alone (1 mg/kg/day; OMP) and in combination with PCP (i.p.), generally produced no changes in 5-HT(2A) receptor protein or mRNA. Hence chronic PCP treatment, as employed here, mimics the decreased 5-HT(2A) receptor binding observed in the PFC of schizophrenic patients. Clozapine's enhancement of the natural response of PCP to down-regulate PFC 5-HT(2A) receptors may contribute to it's improved therapeutic profile against negative symptoms and cognitive deficits.
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PMID:The atypical antipsychotic drug clozapine enhances chronic PCP-induced regulation of prefrontal cortex 5-HT2A receptors. 1538 Mar 71

Abusers of phencyclidine (PCP) often present with a symptom profile similar to that exhibited by schizophrenic patients. Animal models utilising such psychotomimetics are currently informing research into the condition. Accumulating evidence suggests that a central cognitive deficit in schizophrenia is the inability to use task-setting cues to guide goal directed behaviour and that this ability is mediated by prefrontal dopamine (DA). The current study used the non-competitive NMDA antagonist phencyclidine (PCP) and Haloperidol (typical antipsychotic) and Clozapine (atypical antipsychotic) in order to further investigate the influence of DAergic manipulation on a task that requires the use of conditional information to inform goal-directed performance. An instrumental conditional discrimination task was employed in which rats learn to respond appropriately according to the presence of specific auditory conditional stimuli. Probe test 1 showed impaired conditional discrimination performance following sub-chronic PCP administration (seven twice-daily injection protocol) compared to control which was reversed by acute treatment with clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) both administered 60 min pre-test. Probe test 2 (8 days post-treatment) showed enduring deficits to conditional discrimination performance that were again reversed by clozapine but not haloperidol (injection procedures as above). These results show that tasks dependent upon conditional relationships are particularly sensitive to manipulation of DAergic systems as prolonged treatment with PCP has been shown to selectively reduce prefrontal cortex (PFC) DA activity and treatment with clozapine (known to ameliorate cognitive deficits) but not haloperidol has been shown to selectively restore PFC DA levels.
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PMID:Clozapine but not haloperidol treatment reverses sub-chronic phencyclidine-induced disruption of conditional discrimination performance. 1702 93

The novel object recognition (NOR) task is a paradigm employed to detect both disruption and improvement of non-spatial memory in rats. PCP (phencyclidine) may be used to model aspects of schizophrenia symptomology in rats, in particular cognitive deficits. The aim of this study was to investigate the ability of typical and atypical antipsychotics to improve a sub-chronic PCP-induced impairment in cognition using the NOR task. Female hooded-Lister rats (195+/-12 g) received either vehicle (0.9% saline twice daily) or PCP (2 mg/kg, twice daily) for 7 days followed by 7-days drug free. Haloperidol (0.05 and 0.075 mg/kg), clozapine (1 and 5mg/kg), risperidone (0.05, 0.1 and 0.2 mg/kg) or vehicle (veh, saline) was administered i.p. 30 min prior to testing. Rats completed an acquisition trial followed by an inter-trial interval of 1 min, then a retention trial. Following sub-chronic vehicle treatment, rats spent significantly (p<0.05) more time exploring the novel compared to the familiar object, an effect that was abolished in the sub-chronic PCP treated animals. Clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not haloperidol significantly attenuated the PCP-induced impairment such that animals again spent significantly more time exploring the novel compared with familiar object (p<0.05). These results support our earlier work showing that acute PCP induces a robust object recognition deficit in female rats. Clozapine and risperidone but not haloperidol showed efficacy to reverse the deficit induced by sub-chronic PCP suggesting that this test may have some validity for assessing efficacy for improvement of cognitive deficit symptoms of schizophrenia.
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PMID:Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. 1767 72

Neboglamine is a functional modulator of the glycine site on the N-methyl-d-aspartate (NMDA) receptor. Dysfunction of this receptor has been associated with negative and cognitive symptoms in schizophrenia. Thus, we tested the hypothesis that neboglamine behaves as a potential antipsychotic. We compared the effects of neboglamine, D-serine, clozapine, and haloperidol on the expression of Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat forebrain. We also studied the effects of these agents on phencyclidine (PCP)-induced behaviour in rats, a model predictive of potential antipsychotic activity. Neboglamine, like haloperidol and clozapine, significantly increased the number of FLI-positive cells in the prefrontal cortex, nucleus accumbens, and lateral septal nucleus (3.2-, 4.8-, and 4.5-fold over control, respectively). Haloperidol dramatically increased FLI (390-fold over control) in the dorsolateral striatum, a brain region in which neboglamine and clozapine had no effect. The pattern of FLI induced by neboglamine closely matched that of d-serine, an endogenous agonist at the glycine site of NMDA receptors. Consistent with this finding, neboglamine restored NMDA-mediated neurotransmitter release in frontal cortex punches exposed to the NMDA antagonist PCP. In the behavioural model, all test compounds significantly inhibited PCP-induced hyperlocomotion. Unlike haloperidol and clozapine, neither neboglamine nor D-serine affected the basal levels of locomotor activity. Moreover, oral neboglamine dose-dependently inhibited both the hyperlocomotion and the frequency of rearing behaviour induced by PCP. These results, while confirming that the NMDA glycine site is a feasible target for activating the frontostriatal system, support the clinical evaluation of neboglamine as a treatment for schizophrenia.
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PMID:Antipsychotic-like effects of the N-methyl-D-aspartate receptor modulator neboglamine: an immunohistochemical and behavioural study in the rat. 2004 56

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.
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PMID:Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement. 2638 90


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