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) acts as an indirect dopamine (DA) agonist by inhibiting the neuronal reuptake of DA, while it also works as a N-methyl-D-aspartate (NMDA) antagonist. Aiming to investigate characteristics of these two properties of PCP in the same experimental system, the effects of PCP on spontaneous and NMDA-induced efflux of DA from superfused slices of the striatum of the rat were examined. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the samples of superfusate were extracted by alumina extraction and measured by high-performance liquid chromatography with electrochemical detection (HPLC-EC). Phencyclidine at concentrations greater than 1 microM, produced a concentration-dependent increase of the spontaneous efflux of DA. The efflux of DOPAC was also concentration-dependently increased by PCP. However, PCP inhibited the efflux of DA induced by NMDA, even at a small concentration (0.1 microM), which did not alter the spontaneous efflux of the transmitter. The mode of the inhibition by PCP was shown to be noncompetitive, with an estimated IC50 value of 280 nM. These results suggest that PCP, at small concentrations, reduces the synaptic levels of DA by blocking the facilitating effect of endogenous glutamate on the release of DA and, at slightly greater concentrations, the drug also works as an indirect DA agonist, to increase the levels of the transmitter in the synaptic clefts. The clinical significance of the dual effects of PCP is discussed in relation with the unique schizophrenomimetic property of PCP.
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PMID:Effect of phencyclidine on spontaneous and N-methyl-D-aspartate (NMDA)-induced efflux of dopamine from superfused slices of rat striatum. 152 97

At concentrations greater than or equal to 100 microM, phencyclidine (PCP), N-(1-(2-thienyl)-cyclohexyl)piperidine (TCP), and MK-801 induced [3H]dopamine release from dissociated cell cultures of rat mesencephalon. This release was Ca2+ independent and tetrodotoxin insensitive. Tetrodotoxin (2 microM) itself had no effect on spontaneous release of [3H]dopamine. [3H]Dopamine release was induced by 1,3-di(2-tolyl)guanidine, a sigma ligand, and by 4-aminopyridine (1-3 mM), a K+ channel blocker. No stereoselectivity was observed for [3H]dopamine release evoked by the dioxadrol enantiomers, dexoxadrol, and levoxadrol, or by enantiomers of N-allylnormetazocine (SKF 10,047). The selective dopamine uptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909) did not affect spontaneous or TCP-evoked [3H]dopamine release. Together, these data suggest that the dopamine-releasing effects of PCP-like compounds on the mesencephalic cells were not mediated by actions at the PCP receptor or sigma binding site, Ca2+, or Na+ channels, or at the high affinity dopamine uptake site. It remains conceivable that blocking actions of PCP-like compounds at voltage-regulated K+ channels may at least partly explain the response. These results are discussed in comparison with findings in intact brain.
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PMID:Phencyclidine and related compounds evoked [3H]dopamine release from rat mesencephalic cell cultures by a mechanism independent of the phencyclidine receptor, sigma binding site, or dopamine uptake site. 198 Apr 28

The selective D1 and D2-agonists SKF-38393 and N-0437 respectively, were tested in caudate pretreated with PT. A paired recording paradigm was used where the contralateral untreated caudate served as a control. Micropipettes were used to locally apply SKF-38393 and N-0437 onto neurons in both control and PT-pretreated caudate. A significant attenuation of the responses to the D2 agonist were observed after PT administration. Only 1 out of 12 cells tested on the PT side demonstrated any response to locally applied N-0437, whereas 90% of the neurons responded to the drug on the control side. Neurons from both the PT-pretreated and control caudates responded to locally applied SKF-38393. In addition to the specific D1 and D2 receptor agonists, DA and the indirect dopamine agonist PCP were tested for changes in responsiveness. Dopamine was equally efficacious at both control and PT-pretreated caudate neurons, which suggest that dopamine locally applied from the micropipette can interact with the unperturbed D1 receptors in the PT-pretreated caudate. On the other hand, the response to PCP was significantly attenuated after PT administration, which suggest that endogenously released DA preferentially interacts with the D2 receptor subtype. Taken together these data suggest an important role for the D2 receptor in the physiology of dopamine responsiveness in the caudate nucleus.
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PMID:Effects of pertussis toxin on caudate neuron electrophysiology: studies with dopamine D1 and D2 agonists. 198 Nov 69

Uptake of the catecholamines (CA), dopamine (DA) and norepinephrine (NE) into synaptosomes prepared from rat and bovine brains was potentiated by ATP (from 0.1 to 5.0 mM) in a dose-dependent manner. Other nucleotides, particularly the nonhydrolyzable ATP analogs beta,gamma-imidoadenosine-5'-triphosphate (AMP-PNP) and beta,gamma-methyladenosine-5'-triphosphate (AMP-PCP) also potentiated [3H]DA and [3H]NE uptake. Several endogenous 5'-nucleotide triphosphates (e.g. GTP, UTP and CTP) potentiated [3H]CA uptake, but were less effective than ATP. Among the ATP metabolites, only ADP potentiated uptake whereas AMP and adenosine did not. [3H]Dopamine uptake measured in Krebs bicarbonate buffer had a Km of 2.1 microM and a Vmax of 163.9 pmol/mg prot./min. In presence of ATP, [3H]DA uptake had much higher affinity (Km = 0.56 microM) and larger capacity (Vmax = 333 pmol/mg prot./min) than uptake in absence of added ATP. Furthermore, [3H]DA uptake in presence of ATP had faster rate of uptake, and was independent of temperature while in absence of added ATP it was temperature-dependent. This ATP-dependent [3H]DA uptake was retained by synaptosomal ghosts that were obtained after lysing the striatal synaptosomes and removing their contents of synaptic vesicles and mitochondria. It is proposed that, in addition to the carrier-mediated (neuronal) uptake of CA, there is neuronal uptake that is regulated by ATP and inhibited by cocaine, which may be more relevant for terminating the synaptic action of CA because of its faster rate of uptake and larger capacity.
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PMID:ATP-regulated neuronal catecholamine uptake: a new mechanism. 240 89

Pregnant Sprague-Dawley rats were treated with 5 mg/kg body weight of phencyclidine (PCP) injected at 1 ml/kg subcutaneously on three consecutive days at four different stages of gestation. Within 10-30 min after treatment, dams showed some lack of motor coordination and became lethargic. On gestational day 21, all rats were killed by decapitation and brains were dissected and stored from mother and fetus for neurochemical analysis. PCP, dopamine and muscarinic cholinergic receptor binding was measured in membranes prepared from maternal and fetal whole brain. Neurotransmitter concentrations were also measured in the fetal brain homogenates. There was a significant decrease in PCP binding sites in fetal but not maternal brains after maternal PCP injection at gestational days 12-14, 15-17 and 18-20, but not at 9-11 days. Dopamine and muscarinic cholinergic receptor binding was not significantly altered in fetal or maternal brain when compared with vehicle control animals. The whole brain dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid concentrations did not show significant change in any group studied. These data indicate that gestational exposure to PCP decreases high affinity binding of PCP in term fetal brain at doses which do not alter maternal PCP receptor binding.
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PMID:Gestational exposure to phencyclidine (PCP) in rats decreases PCP binding sites in term fetal brain. 285 52

The ability of phencyclidine (PCP), amphetamine and other substances to stimulate dopamine release from and inhibit dopamine uptake into rat striatal synaptosomes was examined in a continuous superfusion system. Inhibition of uptake was measured by determining inhibition of [3H]dopamine displacement by unlabeled dopamine ([1H]dopamine). The displacement of [3H]dopamine by 10(-7) M [1H]dopamine was temperature- and sodium-sensitive and calcium-independent. [1H]Dopamine was an order of magnitude more potent than serotonin or norepinephrine in displacing [3H]dopamine. The concentrations of reserpine required to inhibit [3H]dopamine uptake and [3H]dopamine displacement by [1H]dopamine were similar. Nomifensine, benztropine, PCP and amphetamine also inhibited the displacement of [3H]dopamine by [1H]dopamine at concentrations which have been shown previously to inhibit the uptake of [3H]dopamine, suggesting that the mechanism behind displacement and uptake are very similar. PCP, at 10(-7) to 10(-5) M, significantly inhibited [3H]dopamine displacement by 10(-7) M [1H]dopamine, PCP was less potent than nomifensine or benztropine in inhibiting [3H]-dopamine displacement by 10(-7) M [1H]dopamine, but was equipotent to amphetamine. Superfusion of the synaptosomes for 6 min with PCP, 10(-6)M, induced increases in the spontaneous release of dopamine. In this regard, PCP was less potent than amphetamine, reserpine, flupenthixol, or benztropine. Upon initial exposure of the synaptosomes to amphetamine at 10(-7) to 10(-5) M, a substantial calcium-dependent release of dopamine was induced. In contrast, PCP did not stimulate the early calcium-dependent release of dopamine. These results indicate that PCP is less potent than amphetamine at releasing dopamine and may affect dopamine metabolism in the striatum primarily by inhibiting the reuptake of this catecholamine.
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PMID:Effects of phencyclidine, amphetamine and related compounds on dopamine release from and uptake into striatal synaptosomes. 672 52

d-Amphetamine (DEX) and phencyclidine (PCP) increased motor activity in rats as measured in automated activity cages. Analysis of the stimulation indicated that both drugs increased horizontal activity (total activity), locomotion, and peripheral activity. However, DEX increased while PCP decreased the incidence of rearing. The ability of different drugs to antagonise DEX- and PCP-induced increases in total activity (called stimulation) was measured. Dopamine (DA) D1 receptor antagonists (SCH23390, NNC-01-0112) were 7-8 times more potent in blocking DEX than PCP. DA D2 receptor antagonists (raclopride, remoxipride, haloperidol) were only 1-2 times more potent against DEX-induced stimulation. Nonselective DA receptor antagonists were also tested. Chlorpromazine was more potent against DEX than against PCP. Buspirone and sertindole were slightly more potent in blocking PCP than DEX. Ritanserin (5-HT2 receptor antagonist) was inactive against both stimulants. 8-OH-DPAT (5-HT1A receptor agonist) potentiated the stimulant effects of DEX and PCP. Prazosin (alpha 1-adrenergic receptor antagonist) partially blocked both DEX and PCP. Most drugs tested depressed spontaneous motor activity. Remoxipride and sertindole, however, caused very little depression even at doses several times higher than those needed to block DEX or PCP. The data show clear pharmacological differences between DEX- and PCP-induced stimulation.
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PMID:Dopamine receptor antagonists block amphetamine and phencyclidine-induced motor stimulation in rats. 809 Aug 16

Drugs of abuse, such as phencyclidine (PCP), methamphetamine (METH), and cocaine (COC) are known to affect several behaviors in rats, such as motor activity, stereotypy, and circling. In this study, we evaluated whether these drugs produce circling preferences in the presence or absence of unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the caudate nucleus. Adult male CD rats were lesioned with 10 micrograms 6-OHDA/site. Animals were dosed with PCP (15 mg/kg, ip) its congener (+) MK-801 (0.15 mg/kp, ip), METH (2 mg/kg, ip) COC (60 mg/kp, ip), or apomorphine (0.2 mg/kg, ip). Circling preference was recorded in control and lesioned rats for 2 h before animals were sacrificed to determined monoamine levels by HPLC/EC. In control animals, administration of these drugs produced 60-70% left circling. In lesioned animals, these drugs produced 78-90% ipsilateral (toward the lesion) circling, except apomorphine, which produced 60-80% contralateral (away from the lesion) circling. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly decreased ipsilaterally in lesioned caudate nucleus (CN) and substantia nigra (SN). However, no significant changes were observed in nucleus accumbens (NA) and olfactory tubercles (OT). These data demonstrate that drugs of abuse like PCP, its congener (+) MK-801, METH, and COC produce a greater preference to turn toward the left than the right, a finding similar to that found in human psychosis. Since 6-OHDA lesions enhanced the circling bias and depleted DA and its metabolites DOPAC and HVA, it also suggests that the dopaminergic system may be involved in the circling behavior.
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PMID:Drug-induced circling preference in rats. Correlation with monoamine levels. 856 58

Prepulse inhibition (PPI) of the acoustic startle reflex, a measure of sensory gating, is reduced in schizophrenic patients. Dopamine agonists and NMDA receptor antagonists such as phencyclidine (PCP) can disrupt PPI in animals, consistent with both the dopamine and glutamate hypotheses of schizophrenia. In this study, we sought to further characterize the effects of the NMDA antagonist dizocilpine on acoustic startle modulation. Fischer 344 rats were tested after one of three doses of dizocilpine (0.05, 0.2, and 0.5 mg/kg) and assessed for PPI as well as for alterations in baseline startle and prepulse facilitation (PPF). Results showed complete disruption of PPI for each inhibitory trial type after 0.2 and 0.5 mg/kg of dizocilpine. Baseline startle and PPF were enhanced by the low dose but decreased with the moderate and high doses of dizocilpine. Although dizocilpine caused alterations in prepulse modulation of startle similar to dopamine agonists, some effects differ. Unique effects of dizocilpine on sensory gating are discussed in terms of their potential for discriminating subtypes of schizophrenic illness with different underlying pathophysiology.
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PMID:Effects of the PCP analog dizocilpine on sensory gating: potential relevance to clinical subtypes of schizophrenia. 889 67

The ability to interpret nonverbal facial cues was tested in 10 young white male chronic phencyclidine (PCP) abusers. When their responses were compared with those of age-matched controls, abusers were significantly more accurate in interpreting the facial cues of videotaped medical interns. Phencyclidine abusers tend to form a socially maladroit and downwardly mobile group. However, previous studies of similar maladroit populations such as heroin addicts have indicated that they are less accurate in interpretation of nonverbal facial cues. The complex action of multiple affected neurotransmitters in PCP abusers was examined. Dopamine and serotonin were thought to be the relevant transmitters.
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PMID:Perception of nonverbal facial cues in chronic phencyclidine abusers. 1054 2


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