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)

This study was designed to assess whether phencyclidine (PCP) produces dopamine (DA)-dependent behaviors such as licking, gnawing and biting (which are not observed in normal rats) in rats after pretreatments with a tryptophan hydroxylase inhibitor, p-chlorophenylalanine (PCPA) and specific serotonergic neuronal toxin, p-chloroamphetamine (PCA). Apomorphine (APO, 0.5 mg/kg) and methamphetamine (MAP, 2.5 mg/kg) mainly induced DA-dependent behaviors, including rearing and sniffing with occasional licking, in the vehicle-pretreated rats. APO (0.5 mg/kg)-induced DA-dependent behaviors significantly increased in the PCA- and PCPA-pretreated rats, in which serotonergic activity was greatly depressed but dopaminergic activity was normal. MAP (2.5 mg/kg)-induced DA-dependent behaviors were also significantly increased in the PCA-pretreated rats but not PCPA-pretreated rats. On the other hand, at doses of 2.5-7.5 mg/kg, PCP mainly caused stereotyped behaviors such as head-weaving, backpedalling, turning and DA-dependent behavior, such as sniffing, in the vehicle-pretreated rats. The PCP-induced stereotyped behaviors were attenuated by pretreatment with PCA and PCPA. In contrast, PCP-induced DA-dependent behavior, sniffing, was converted into more intense behaviors such as licking, gnawing and biting by pretreatment with PCA. These effects of PCP were also observed in rats pretreated with PCPA, although the degree was less than that by pretreatment with PCA. These results may indicate that serotonergic neuronal systems inhibitory regulate dopaminergic systems in PCP-induced behavioral responses.
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PMID:Potentiation of phencyclidine-induced dopamine-dependent behaviors in rats after pretreatments with serotonin-depletors. 294 1

During cardiac surgery treatment of deterioration of myocardial function is usually based on catecholamines. Development of selective phosphodiesterase-(PDE-)III-inhibitors seems to be a new aspect in treating myocardial dysfunction. Therefore the hemodynamic effects of the new PDE-inhibitor enoximone were investigated in 20 coronary surgery patients unable to be weaned from extracorporeal circulation (ECC) without pharmacological intervention (MAP less than 60 mmHg, CI less than 2.00 l/min.m2, PCP greater than 15 mmHg). After controlled reperfusion with 2.4 1/min.m2 two groups were separated in a random sequence receiving either 0.5 mg/kg enoximone as a bolus (n = 10), or dobutamine (n = 10, 5 micrograms/kg.min) as perfusion. In the dobutamine-group MAP and CI (-14%) were decreased, while HR was increased significantly (+30%). Application of enoximone was followed by a slight increase in CI (+5%), a significant decrease in TSR while HR remained almost unchanged. PCP, too, differed significantly between the groups (enoximone: -38%; dobutamine: -10%). Ten minutes after weaning from ECC additional pharmacologic therapy (calcium, vasodilators, epinephrine) was necessary in eight dobutamine treated patients in contrast to four patients in the enoximone group (calcium, epinephrine). In patients with impaired myocardial performance during weaning from ECC enoximone seems to be an alternative therapy and is judged to be of some advantage compared to dobutamine application in this situation. The mechanism for improvement appears to be enhanced contractility owing to its positive inotropic effects, as well as a decrease in left ventricular outflow resistance resulting from peripheral vasodilation.
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PMID:[Enoximone, a new phosphodiesterase inhibitor: the spectrum of applications during heart surgery--a comparison with dobutamine]. 297 97

We investigated whether risperidone, a 5-HT2/dopamine-D2 receptor antagonist, inhibits the development of tolerance and supersensitivity to PCP and whether subacute administration of PCP with risperidone affects the [3H]MK-801 binding in rat brain, in comparison with dopamine-D2 receptor antagonist haloperidol and 5-HT2 receptor antagonist ritanserin. In rats treated with PCP (10 mg/kg, i.p.) for 14 days, PCP (10 mg/kg, i.p.)-induced hyperlocomotion, rearing and sniffing were potentiated (supersensitivity), and head-weaving, head-twitch, backpedalling and turning were diminished (tolerance). The development of supersensitivity to PCP was blocked by oral co-administration of risperidone (2.4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) for 14 days, but not ritanserin (10 mg/kg, p.o.) and risperidone (0.8 mg/kg, p.o.), while no drugs prevented the development of tolerance to PCP. Both risperidone (2.4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) also inhibited the cross-supersensitivity to methamphetamine (MAP; 2.5 mg/kg, i.p.)-induced rearing in rats treated with PCP for 14 days. The profiles of [3H]MK-801 binding in discrete brain areas did not change after subacute administration of PCP alone or in combination with risperidone, haloperidol or ritanserin for 14 days. Therefore, it is suggested that subacute administration of PCP may cause functional changes in the dopaminergic neuronal transmission under conditions where the binding of [3H]MK-801 in discrete brain areas is unchanged, and that co-administration of risperidone may block these PCP-induced changes in neuronal function.
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PMID:Risperidone prevents the development of supersensitivity, but not tolerance, to phencyclidine in rats treated with subacute phencyclidine. 753 75

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

The abnormal behaviors induced by methamphetamine (MAP: 1 mg/kg) or phencyclidine (PCP: 10 mg/kg) were measured using behavioral analysis following the microinjection of one of three calcium (Ca) antagonists (nifedipine: Nif, nicardipine: Nic and flunarizine: Flu) into the rat caudate putamen or amygdala. The intraperitoneal administration of MAP or PCP induced abnormal behaviors in a time-dependent manner; the maximum locomotor activity was measured 30-45 min after the administration of MAP or PCP. This hyperactivity was sustained for more than 2 h. Following microinjection of these Ca antagonists into the caudate putamen, each showed a different pattern of inhibition on MAP- or PCP-induced abnormal behaviors. Nic and Flu were effective at reducing these abnormal behaviors, in contrast, Nif was ineffective. In particular, the inhibitory effect of Nic was stronger than that of Flu. Microinjection of these Ca antagonists into the amygdala did not show any reductive effect on the hyperactivity induced by MAP or PCP. These results demonstrate that these Ca antagonists have different pharmacological properties and that both L- and T-type Ca2+ channels modulate the dopamine release in the rat caudate putamen. These results further lead us to suggest the presence of a subtype of L-type Ca2+ channels in the caudate putamen.
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PMID:Differentiation of the inhibitory effects of calcium antagonists on abnormal behaviors induced by methamphetamine or phencyclidine. 956 18

Activated p38gamma MAP kinase exhibited significant basal ATPase activity in the absence of a kinase substrate, and addition of a phosphoacceptor substrate increased k(cat)/K(m)20-fold. AMP-PCP was competitive with ATP binding and non-competitive with phosphoacceptor substrate binding. The nucleotide binding site affinity label 5'-(p-fluorosulfonylbenzoyl)adenosine (FSBA) bound stoichiometrically at Lys-56 in the ATP site of both unphosphorylated and activated p38gamma. AMP-PCP only protected the activated enzyme from FSBA inactivation, implying that AMP-PCP does not bind unphosphorylated p38gamma. Basal ATPase activities were also observed for activated p38alpha, ERK2 and JNK3 suggesting that the enzymatic mechanism may be similar for all classes of MAP kinases.
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PMID:Kinetic mechanism and ATP-binding site reactivity of p38gamma MAP kinase. 1056 20

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.
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PMID:Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain. 1116 17

Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the Kd, but not Bmax, values of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) binding to adenosine A1 receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the Kd and Bmax values of [3H]DPCPX binding to adenosine A1 receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the Bmax and Kd values of [3H]2-p-(2-carboxyehyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine ([3H]CGS21680) binding to adenosine A2A receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [3H]CGS21680 to adenosine A2A receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A2A receptors, but not adenosine A1 receptors in rat brain.
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PMID:Subchronic treatment with methamphetamine and phencyclidine differentially alters the adenosine A1 and A2A receptors in the prefrontal cortex, hippocampus, and striatum of the rat. 1149 46

The purpose of this study was to compare the effects of systemically administered MAP with those of phencyclidine (PCP), both of which induced comparable locomotor activity, on firing activity of medial prefrontal cortex (mPFC) neurons in freely moving rats. The results show that, unlike PCP, acutely administered MAP produced little changes in firing activity of mPFC neurons.
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PMID:Different effects of phencyclidine and methamphetamine on firing activity of medial prefrontal cortex neurons in freely moving rats. 1254 74

Knockdown studies in Xenopus demonstrated that the XMeis3 gene is required for proper hindbrain formation. An explant assay was developed to distinguish between autonomous and inductive activities of XMeis3 protein. Animal cap explants caudalized by XMeis3 were recombined with explants neuralized by the BMP dominant-negative receptor protein. XMeis3-expressing cells induced convergent extension cell elongations in juxtaposed neuralized explants. Elongated explants expressed hindbrain and primary neuron markers, and anterior neural marker expression was extinguished. Cell elongation was dependent on FGF/MAP-kinase and Wnt-PCP activities. XMeis3 activates FGF/MAP-kinase signaling, which then modulates the PCP pathway. In this manner, XMeis3 protein establishes a hindbrain-inducing center that determines anteroposterior patterning in the brain.
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PMID:Xenopus Meis3 protein forms a hindbrain-inducing center by activating FGF/MAP kinase and PCP pathways. 1466 Apr 37


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