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)

A variety of neuroleptics were compared for their ability to block phencyclidine (PCP)-induced behavioral stimulation in mice. Methiothepin, fluphenazine, trifluoperazine, and chlorpromazine were highly effective in blocking phencyclidine-induced stimulation at doses that did not decrease spontaneous behavioral activity. Clozapine, thioridazine and haloperidol were moderately effective, while sulpiride, molindone, and pimozide were completely ineffective. The effectiveness of the drugs was found to be correlated with their ability to block tryptamine-induced seizures and with several other measures of antidopaminergic and antiserotonergic potency. it is concluded that a combination of antidopaminergic and antiserotonergic activity is important for blocking the stimulating effects of phencyclidine.
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PMID:Effects of neuroleptics on phencyclidine (PCP)-induced locomotor stimulation in mice. 614 71

The effect of various typical (haloperidol) and atypical (clozapine, raclopride, remoxipride) antipsychotics on phencyclidine (PCP)-induced disruption of sensorimotor gating was tested in rats using an acoustic startle paradigm. Clozapine (4-40 mumol/kg), haloperidol (1-5 mumol/kg) and raclopride (1-12 mumol/kg) failed to reverse PCP-induced disruption of prepulse inhibition (PPI) of the acoustic startle response. In contrast, remoxipride (12-60 mumol/kg) caused a dose-dependent block of this effect. PCP-induced disruption of PPI is a widely accepted animal model of a corresponding behavioural deficit observed in schizophrenia although little evidence has been presented that it is in fact sensitive to antipsychotic agents. The present results indicate that remoxipride behaves in a unique way in this model compared to clozapine, haloperidol and raclopride.
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PMID:The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat. 770 Oct 46

Previous work has shown that phencyclidine (PCP) and amphetamine decrease social behavior in rats. The purpose of the present study was to determine the effects of the dopamine antagonists clozapine and haloperidol on PCP- and amphetamine-induced changes in rat social behavior. An intruder paradigm was used, in which rats were injected with drug and placed into a stable home colony of three other rats. Social behaviors were recorded for 30 min. Both amphetamine (4.0 mg/kg) and PCP (4.0 mg/kg) substantially reduced social behavior. Haloperidol and clozapine did not produce a general reversal of the effects of amphetamine or PCP on the total number of social behaviors. Nevertheless, 0.025 mg/kg haloperidol did reverse the effects of PCP and amphetamine on some of the specific social behaviors observed (side threats, mounting, crawling under). Clozapine had no effect on reversing the actions of amphetamine on social behavior, but 2.0 mg/kg clozapine did reverse the effect of PCP on side threats and mounting. These results indicate that DA antagonists do not restore normal social behavior in animals treated with PCP or amphetamine, but can reverse some of the effects of PCP or amphetamine on specific social behaviors.
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PMID:The effects of haloperidol and clozapine on PCP- and amphetamine-induced suppression of social behavior in the rat. 820 77

Phencylidine (PCP) is a psychotomimetic noncompetitive glutamate antagonist that has been used in studies of the neural substrates of psychosis. Both schizophrenic patients and PCP-treated rats exhibit reduced amounts of prepulse inhibition (PPI) of the startle reflex, which is the normal inhibition of startle that occurs when the starting noise is preceded 30 to 500 msec by a weak prepulse. The present study assessed the effects of seroquel (ICI 204,636), a mixed D2/5-hydroxytryptamine2 antagonist with a preclinical profile suggestive of potential antipsychotic efficacy, on the PCP-induced disruption of PPI. Clozapine, risperidone and haloperidol were also studied as comparison compounds. PCP (1.25 mg/kg) significantly reduced PPI, with prepulses that were 1 to 12 dB above background. Seroquel and clozapine significantly restored PPI in PCP-treated rats, whereas haloperidol and risperidone did not. Similar findings were obtained in studies using separate animals, a slightly lower dose of PCP (1.0 mg/kg) and a high dose of each of these antipsychotics. Separate studies verified that risperidone and haloperidol restored PPI in apomorphine-treated rats. In the present studies, seroquel exhibited a profile consistent with those exhibited by other "atypical" antipsychotics.
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PMID:Seroquel restores sensorimotor gating in phencyclidine-treated rats. 896 53

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

A series of six experiments were conducted to determine the effects of haloperidol, clozapine, olanzapine, and phencyclidine (PCP) on rotorod performance. Rodents were trained to walk on a rotorod to avoid a mild shock to a criterion of 20 rpm for 3 min. None of the vehicles of any of these drugs disrupted rotorod performance. Haloperidol disrupted rotorod performance at doses of 0.03, 0.1, and 0.3 mg/kg, and olanzapine disrupted rotorod performance at doses of 3.0 and 10.0 mg/kg. Clozapine produced a much milder disruption across all three doses (3.0, 10.0, and 30.0 mg/kg). PCP produced a consistent and severe disruption of rotorod performance at doses of 4.0 and 6.0 mg/kg, but not at a dose of 2.0 mg/kg. Twenty-four hours postinjection there were no residual PCP effects on rotorod performance. Coadministration of either haloperidol or olanzapine with PCP did not reverse PCP-induced disruption in rotorod performance, while clozapine produced a partial reversal at only one dose. These findings indicate that olanzapine functions similarly to classic antipsychotics with respect to their effects on locomotion and balance.
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PMID:The effects of atypical antipsychotics and phencyclidine (PCP) on rotorod performance. 1041 78

Previous animal studies have indicated that drugs targeted at metabotropic glutamate (mGlu) receptors may be useful for treatment of psychosis. In this article, the effects of the novel, potent, and selective mGlu2/3 receptor agonists LY354740 and LY379268, and the clinically effective agents clozapine and haloperidol, were investigated using phencyclidine (PCP; 5 mg/kg)- versus d-amphetamine (AMP; 3 mg/kg)-evoked motor activities. LY354740 (1-10 mg/kg s.c.), LY379268 (0.3-3 mg/kg s.c.), clozapine (1-10 mg/kg s.c.), and haloperidol (0.03-1 mg/kg s.c.) reversed the increases in ambulations, fine motor (nonambulatory) movements, and decreased time at rest evoked by PCP. Furthermore, the inhibitions of the PCP response by the mGlu2/3 agonist LY379268, but not by clozapine, were completely reversed by the selective mGlu2/3 receptor antagonist LY341495. Doses of LY354740 and LY379268 that blocked the effects on PCP had no effects on rotorod performance, and (with the exception of rearing behavior) had minimal effects on AMP-evoked motor activities. Clozapine blocked AMP-induced rearing but enhanced AMP-induced ambulations and fine movements at the lower doses (1 and 3 mg/kg). Unlike the mGlu2/3 agonists, the highest dose of clozapine tested (10 mg/kg) impaired animals on the rotorod. Haloperidol potently blocked all PCP and AMP effects, but only at doses associated with motor impairment. These data demonstrate that mGlu2/3 receptor agonists act via a unique mechanism to selectively block PCP-induced behaviors. Moreover, the marked mGlu2/3 receptor-mediated inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with minimal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.
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PMID:The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. 1049 Sep

The effect of atypical antipsychotics on the immediate-early gene, arc (activity-regulated cytoskeleton-associated gene), expression was investigated in phencyclidine (PCP)-treated rats using RT-PCR. Administration of PCP (10 mg/kg) increased arc mRNA levels in the prefrontal cortex, nucleus accumbens and posterior cingulate cortex. Pretreatment with clozapine (20 mg/kg), olanzapine (10 mg/kg) and risperidone (2 mg/kg), but not haloperidol (2 mg/kg), prevented PCP-induced arc expression in the prefrontal cortex and nucleus accumbens. Pretreatment of haloperidol increased the striatal arc mRNA levels. Clozapine, olanzapine and haloperidol inhibited the PCP-induced arc expression in the posterior cingulate cortex. These results suggest that the effects of antipsychotic drugs on PCP-induced arc expression in the prefrontal cortex and nucleus accumbens are useful for distinguishing atypical antipsychotic properties of the drugs.
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PMID:Effect of atypical antipsychotics on phencyclidine-induced expression of arc in rat brain. 1071 13

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

Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.
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PMID:Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. 1258 79


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