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 behavioural study on the effects of D1 and D2 dopamine receptor antagonists (SCH 23390 and sulpiride respectively) and of an A1 adenosine receptor agonist (N6-L-phenylisopropyladenosine, L-PIA) against phencyclidine (PCP)-induced effects was assessed in adult male rabbits. SCH 23390 (0.003-0.01 mg/kg i.v.) and sulpiride (12.5 mg/kg i.v.) were able to significantly prevent PCP-induced stereotypy. Ataxia was reduced by SCH 23390 (0.003 mg/kg i.v.), while it was potentiated by sulpiride (12.5 mg/kg i.v.). Given alone at 12.5 mg/kg, sulpiride induced some EEG and behavioural effects in rabbits, while SCH 23390 (0.003 and 0.01 mg/kg) did not. L-PIA prevented both PCP-induced stereotypy and ataxia at the dose (0.1 mg/kg i.v.) devoid of behavioural or EEG effects by itself. Our results suggest that D1 dopamine receptors might play a more important role than D2 receptors in the expression of PCP-induced behaviour. They also propose that A1 adenosine receptors might be involved (e.g. via an influence on the dopamine release) in the behavioural effects of PCP.
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PMID:Evidence of the involvement of D1 dopamine receptors in PCP-induced stereotypy and ataxia in rabbits. 218 22

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.
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PMID:Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. 748 May 37

Although phencyclidine (PCP) has several neurochemical effects, the most pharmacologically relevant are thought to be its ability to antagonize the activity of N-methyl-D-aspartate (NMDA)-type glutamate receptors and to increase extracellular dopamine concentrations. In order to elucidate the nature and consequence of PCP actions on glutamatergic and dopaminergic pathways, this study examined the response of extrapyramidal and limbic neurotensin systems to this drug. Multiple, but not single, doses of PCP caused increases in striatal neurotensin-like immunoreactivity content of 150-200% of control. These effects were blocked by the dopamine D1 receptor antagonist, SCH 23390, suggesting they were caused by PCP-mediated enhanced dopamine activity at dopamine D1 receptors. In contrast, MK-801 (dizocilpine), a selective NMDA receptor antagonist that acts at the same site as PCP, had no effect on neurotensin-like immunoreactivity content when given alone. In addition, coadministration of MK-801 with PCP did not alter the effect of PCP on striatal neurotensin-like immunoreactivity content. This lack of effect suggests that the actions of PCP on NMDA receptors was not involved in the neurotensin response. The PCP effect on neurotensin striatal pathways also appeared not to be associated with the dopamine D2 or gamma-aminobutyric acid (GABA) systems: a possible role for the sigma receptor in this effect could not be eliminated. Administration of multiple doses of PCP also affected neurotensin-like immunoreactivity content in the nucleus accumbens (160% compared to control) and frontal cortex (40% compared to control), but not the substantia nigra. The neurotensin effects of PCP are compared to those of another psychotomimetic drug of abuse, methamphetamine.
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PMID:Response of extrapyramidal and limbic neurotensin systems to phencyclidine treatment. 767 1

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, MK-801, and phencyclidine (PCP), induce the HSP70 heat shock or stress gene in pyramidal neurons in rat posterior cingulate and retrosplenial cortex. PCP also induces HSP70 in many other pyramidal neurons in brain including neocortex, insular cortex, piriform cortex, hippocampus, and basal nuclei of the amygdala. Several neurotransmitter antagonists, including haloperidol, clozapine, SCH-22390, diazepam, and muscimol, inhibited induction of HSP70 produced by PCP. Baclofen had no effect. Nifedipine blocked induction of HSP70 by PCP in cingulate, neocortex, and insular cortex but only partially blocked HSP70 in piriform cortex and amygdala. These data suggest that phencyclidine injures pyramidal neurons via dopamine D1, D2, D4, sigma, and other receptors. Gamma-aminobutyric acid (GABA) agonists ameliorate the injury. A model is proposed whereby NMDA receptor blockade on GABA neurons decreases inhibitory inputs onto cortical pyramidal neurons and makes them more vulnerable to injury from a variety of excitatory inputs. It is possible that psychosis produced by PCP and other NMDA antagonists correlates with overactivity and eventual injury to cingulate pyramidal neurons.
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PMID:Neuronal injury produced by NMDA antagonists can be detected using heat shock proteins and can be blocked with antipsychotics. 777 Jun 20

Behavioral effects of PCP-type noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (-)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([3H]MK-801) but not sigma([3H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), sigma receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists.
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PMID:Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists. 785 18

Neuropeptide Y-like immunoreactivity (NPYLI) in the frontal cortex and nucleus accumbens was significantly decreased after acute and multiple administrations of phencyclidine-HCl (PCP). The role of dopamine, serotonin and sigma receptors in these PCP-induced effects was evaluated. Neither the dopamine D1 antagonist SCH 23390 nor the D2 antagonist sulpiride by itself altered cortical neuropeptide systems, but in combination they totally blocked the PCP-induced changes. In contrast, sulpiride alone significantly decreased accumbens NPYLI content and enhanced the PCP-induced decreases, whereas SCH 23390 alone had no effect on accumbens NPYLI levels but did attenuate PCP-induced effects. Neither depletion of serotonin nor blockage of the sigma "receptor" had any effect on PCP-induced changes in either structure. The effects of the selective, noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 on cortical and accumbens NPYLI content were similar to those of PCP, suggesting an N-methyl-D-aspartate receptor mechanism in these effects. Administration of gamma-aminobutyric acid-transaminase (GABA-T) inhibitors, gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) or aminooxyacetic acid alone had no effect on cortical NPYLI content; however, administration of aminooxyacetic acid alone decreased accumbens NPYLI levels. Co-administration of these GABA-T inhibitors with PCP completely blocked PCP-induced cortical NPYLI decreases and attenuated NPYLI changes in the accumbens. These data suggest that limbic neuropeptide systems are differentially modulated by N-methyl-D-aspartate and dopaminergic activity and that glutamatergic influences on cortical and accumbens NPY systems are mediated, at least in part, by GABAergic mechanisms.
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PMID:Differential regulation of neuropeptide Y systems in limbic structures of the rat. 824 45

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male mice with haloperidol (0.1 mg/kg, i.p.) completely prevented the stimulation of normally coordinated locomotion induced by a non-intoxicating dose of dizocilpine (0.1 mg/kg, i.p.); haloperidol also attenuated the locomotor stimulation produced by phencyclidine (PCP, 1 and 2 mg/kg, i.p.), d-amphetamine (2 and 5 mg/kg, i.p.) and diazepam (0.5 mg/kg, i.p.). Haloperidol (doses up to 2.5 mg/kg) did not attenuate the ataxia and decreased locomotion induced by higher doses of dizocilpine (1 and 2 mg/kg). The active cis isomer of flupenthixol (0.5 mg/kg, i.p.), an antagonist of both D1 and D2 dopamine receptors, also diminished the stimulant actions of all of the test drugs, whereas its inactive trans form did not. The selective D1 antagonist R(+/-)-SCH 23390 (0.1 mg/kg) and the selective D2 antagonist raclopride (1 mg/kg) had little effect on the stimulatory effect of dizocilpine, although they did reduce the stimulation produced by PCP, d-amphetamine and diazepam. However, pretreatment with a combination of R(+/-)SCH 23390 and raclopride completely prevented dizocilpine-induced locomotor stimulation. Pretreatment with alpha-methyl-p-tyrosine (AMPT, 50 and 250 mg/kg), an inhibitor of tyrosine hydroxylase, or with 6-hydroxydopamine (6-OH-DA, 50 micrograms, i.c.v.), a neurotoxin that destroys brain dopaminergic and noradrenergic neurons, did not attenuate the locomotor stimulation induced by dizocilpine, although these treatments did reduce the stimulant effects of d-amphetamine. In AMPT or 6-OH-DA pretreated mice, haloperidol (0.125 mg/kg) prevented the stimulatory effect of dizocilpine. These results support a role for dopamine receptors in the stimulation of normally coordinated locomotion by dizocilpine. However, the locomotor stimulant effect of dizocilpine, unlike that of d-amphetamine, can be expressed in the presence of D1 or D2 dopamine receptor blockade and does not appear to be dependent on intact presynaptic mechanisms.
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PMID:Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice. 856 5

Local perfusion with phencyclidine (PCP) increased extracellular dopamine levels in the rat striatum in a dose-dependent manner, as measured by in vivo microdialysis. While pretreatment with SCH 23390, a selective dopamine D1 receptor antagonist, had no significant effect on PCP-induced increases in extracellular dopamine levels, pretreatment with YM-09151-2 (cis-N-(1- benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylamin obenzamide), a selective dopamine D2 receptor antagonist, markedly potentiated the effect of PCP. These results suggest that the blockade of dopamine D2 presynaptic autoreceptors strongly potentiates the PCP-induced dopamine release in the striatum.
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PMID:Potentiation of phencyclidine-induced dopamine release in the rat striatum by the blockade of dopamine D2 receptor. 857 18

The effects of dopamine receptor antagonists on phencyclidine (PCP)-induced behaviors were examined in rats. Acute administration with PCP (7.5 mg/kg i.p.) produced various behavioral changes, such as increases of spontaneous activity, head-weaving, sniffing, rearing, back-pedaling, and ataxia. To determine which dopamine receptor subtypes were involved in mediating the PCP-induced behaviors, SCH 23390 (0.05 and 0.5 mg/kg), sulpiride (20 and 100 mg/kg), or haloperidol (0.05 and 0.5 mg/kg) were pretreated 30 min before PCP treatment (7.5 mg/kg). A higher dose of SCH 23390 significantly reduced the increase of spontaneous activity induced by PCP. Both doses of sulpiride did not affect the PCP-induced behaviors. A higher dose of haloperidol decreased the PCP-induced spontaneous activity, whereas a lower dose of haloperidol enhanced the activity. Ketanserin (0.5 and 5 mg/kg) did not alter any PCP-induced behaviors. These results suggest that the D1, but not D2, dopamine receptor subtype may be involved in the PCP-induced behavioral abnormality.
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PMID:Involvement of dopamine D1 receptors in phencyclidine-induced behavioral stimulation in rats. 866 36

Psychotic-like behaviour was induced in rats with a single i.p. injection of AMPH (20 mg/kg b.w.) and/or PCP (10 mg/kg b.w.). The D1 and D2 dopamine receptor (DAR) specific binding of [3H]SCH 23390 and [3H]spiperone, respectively, during the 120 min period upon the treatment was examined on cryosections using computerized scanning and image analysis. AMPH, alone or in combination with PCP, induced a transient decrease of the D1 receptor specific binding in the striatum (30 min; AMPH, -18%; AMPH+PCP, -31%) and nucleus accumbens (30 min; AMPH, -30%; AMPH+PCP, -40%), which was completely abolished at the 120 min point. Only AMPH persistently elevated nigral D1 receptor specific binding. PCP-induced striatal and accumbal D1 receptor down-regulation was intensive throughout the 120 min period, while in the s. nigra it was non-significant. A significant increase of the D2 receptor specific binding was observed only 30 min after the treatment in striatum (AMPH, 15%; PCP, 16%; AMPH+PCP, 13%) and n. accumbens (AMPH, 16%). These alterations of DAR specific binding may reflect a regulation of the DAR and the changes in nigrostriatal and mesolimbic DA-ergic neurotransmission during an intensive drug-induced psychotic-like behavioral expression.
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PMID:Acute amphetamine and/or phencyclidine effects on the dopamine receptor specific binding in the rat brain. 944 62


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