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)

This study sought to determine whether the reported lead-induced inhibition of binding of the non-competitive NMDA receptor complex antagonist, MK-801, was of sufficient biological strength and relevance to produce changes in MK-801 behavioral sensitivity. Rats were chronically exposed from weaning to levels of 0, 50 or 150 ppm lead (Pb) acetate in drinking water and trained to discriminate the stimulus properties of 0.05 mg/kg MK-801 from saline at 2 months of age using a standard operant food-reinforced drug discrimination paradigm. Following acquisition of the discrimination, various doses of MK-801, of the non-competitive antagonist phencyclidine (PCP), the competitive antagonist CPP, and of NMDA, were substituted for 0.05 mg/kg MK-801 and percent MK-801 lever responding to each determined. Increasing doses of MK-801 and of PCP produced dose-related increases in MK-801 lever responding to levels exceeding 90%, whereas CPP produced levels less than 50 percent. NMDA produced primarily saline lever responding. Pb exposure was associated with MK-801 subsensitivity as indicated by downward and/or right-shifts of the MK-801 dose-effect curve, and by attenuated MK-801 lever responding following an MK-801 washout period. No Pb-related changes in sensitivity to PCP, CPP or NMDA were observed. These data provide in vivo support for the possibility that glutamatergic system changes could be involved in the behavioral toxicity produced by lead exposure.
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PMID:MK-801 subsensitivity following postweaning lead exposure. 760 48

The non-competitive NMDA antagonist ketamine, given to schizophrenic individuals in subanesthetic doses, produced a short-lived, discrete activation of their psychotic symptoms, which had striking similarities to symptoms of their usual psychotic episodes. To further study this psychotomimetic property of ketamine, we administered 0.3 mg kg-1 of the drug to schizophrenic individuals during a [15O] water cerebral blood flow study. Regional cerebral blood flow (rCBF) was measured using H2(15)O and positron emission tomography (PET) before and after ketamine administration to identify regions of flow change, rCBF was increased in anterior cingulate cortex and was reduced in the hippocampus and primary visual cortex (lingual and fusiform gyri). These data encourage further consideration of altered glutamatergic transmission in schizophrenic and PCP-induced psychoses.
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PMID:Ketamine activates psychosis and alters limbic blood flow in schizophrenia. 761 73

The role of sigma receptors in antinociceptive processes remains equivocal, because previous sigma drugs also bind to PCP/NMDA and opiate receptors. The present study examined the antinociceptive effects of the high-affinity, sigma-selective ligand 1,3-di-o-tolylguanidine (DTG; 10, 15, and 20 mg/kg, IP) on tail-withdrawal latencies in mice. DTG produced significant but short-lived increases in withdrawal latencies at all dose levels. DTG also produced hypothermia, but this effect was dissociable from antinociception. The highly selective sigma ligand rimcazole (10 and 25 mg/kg, IP) antagonized DTG antinociception in a dose-dependent manner. The opiate antagonist naloxone and the PCP/NMDA antagonist MK-801 were, however, without effect. Haloperidol, which also binds to sigma receptors, increased withdrawal latencies but did not alter DTG antinociception. These data implicate sigma receptors as the site of DTG antinociception, and more generally support the distinction between sigma, opiate, and PCP/NMDA receptors.
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PMID:Antinociception following 1,3,-di-o-tolylguanidine, a selective sigma receptor ligand. 761 5

Capsaicin in the adult animal causes antinociception due to the massive release of neurotransmitters, including substance P (SP), from primary afferent C-fibers. The results of the present study indicate that capsaicin-induced antinociception in the adult is sensitive to inhibition by dizocilpine (MK-801). The failure of a high dose (10 nmoles) of (+-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) to mimic the effect of MK-801 (1 nmole) on antinociception induced by 0.8 micrograms of capsaicin suggests that the inhibition by MK-801 is mediated by a phencyclidine (PCP) site but is not associated with NMDA activity. The inability of haloperidol (1 nmole) to affect the actions of capsaicin argues against an interaction with sigma sites. Behavioral sensitization to intrathecally administered kainic acid (KA) has been proposed to reflect similar neuronal activity to that underlying pain transmission. KA sensitization is inhibited by pretreatment with capsaicin (0.8 microgram) or SP(1-7) (10 nmoles) and the influence of MK-801, CPP and haloperidol on these inhibitory effects of capsaicin and SP(1-7) were identical to those on capsaicin-induced antinociception. These data are consistent with the hypothesis that the antinociceptive effect of capsaicin in the adult is similar to that of the N-terminus of SP, both of which involve a pathway sensitive to MK-801 but not mediated by NMDA-type activity.
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PMID:MK-801 inhibits the effects of capsaicin in the adult mouse by an action involving phencyclidine (PCP) sites not linked to NMDA activity. 769 10

Intraperitoneal administration of clonidine (50 micrograms/kg) produced increases in growth hormone levels in male Wistar rats. Pretreatment with NMDA receptor antagonists including (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP/NMDA site), ifenprodril (polyamine site), and dizocilpine maleate (MK-801) or phencyclidine (PCP) (channel blockers) did not have any significant effect on clonidine-induced increases in growth hormone levels. In contrast, pretreatment with 5,7-dichlorokynurenic acid and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (NMDA receptor-associated glycine site antagonists) significantly attenuated clonidine-induced increases in growth hormone levels. Attenuation of clonidine's effect on growth hormone levels by NMDA receptor-associated glycine site antagonists appears most likely due to an interaction between their effects on the NMDA receptor complex with growth hormone releasing factor.
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PMID:The NMDA receptor complex modulates clonidine-induced increases in growth hormone levels in rats. 774 72

Behavioral and in vitro receptor binding methods were used to evaluate and compare the effects of FR115427 ((+)-l-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) with those of MK801, a non-competitive NMDA antagonist. FR115427 inhibited NMDA-induced convulsions in mice by intracerebroventrical(ICV) and systematic injection. FR115427 was found to be about ten times less potent than MK801. Furthermore, the inhibitory effect of FR115427 and MK801 on NMDA-induced convulsions was evaluated in time course studies in mice. MK801 exhibited a more sustained anticonvulsive activity than FR115427. In addition, PCP-like behaviors were examined in mice after ICV injection of these compounds. At the lowest dose FR115427 significantly increased locomotor activity, although the effect of this compound was about hundred times less potent than that of MK801. At higher dose a more complex pattern of behavior, e.g. head-movement and eventually ataxia was observed. In binding assays with rat brain membranes, FR115427 inhibited the binding of (3H)TCP (IC50 = 0.249 microM) and (3H)MK801 (IC50 = 0.312 microM) but did not inhibit the binding of (3H)CPP or (3H)glycine. These results suggest that FR115427 is a novel non-competitive NMDA antagonist that acts on a binding site located within the NMDA receptor associated ion channel.
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PMID:Behavioral studies on FR115427, a novel selective N-methyl-D-aspartate antagonist. 775 64

Substantiating evidence has raised the possibility that sigma ligands may have therapeutic potential as neuroprotective agents in brain ischemia. It has been suggested that the neuroprotective capacity of sigma ligands is related primarily to their affinity for the NMDA receptor complex and not to any selective action at the sigma binding site. However, sigma specific ligands, devoid of significant affinity for the NMDA receptor, are also neuroprotective via an inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. In the present study, we have investigated the potential neuroprotective effect of a comprehensive series of sigma ligands, with either significant (sigma/PCP) or negligible (sigma) affinity for the PCP site of the NMDA receptor, in order to delineate a selective sigma site-dependent neuroprotective effect. For this aim, we have employed two different neuronal culture toxicity paradigms implicating either postsynaptic-mediated neurotoxicity, (brief exposure of cultures to a low concentration of NMDA or Kainate) or pre- and postsynaptic mechanisms (exposure to hypoxic/hypoglycemic conditions). Only sigma ligands with affinity for the NMDA receptor [(+) and (-) cyclazocine, (+) pentazocine, (+) SKF-10047, ifenprodil and haloperidol] were capable of attenuating NMDA-induced toxicity whereas the sigma [(+)BMY-14802, DTG, JO1784, JO1783, and (+)3-PPP] and kappa-opioid [CI-977, U-50488H] ligands, with very low affinity for the NMDA receptor, were inactive. The rank order of potency, based on the 50% protective concentration (PC50) value, of sigma/PCP ligands against NMDA-mediated neurotoxicity correlates with their affinity for the PCP site of the NMDA receptor, and not with their affinity for the sigma site. In addition sigma/PCP, sigma or kappa-opioid ligands failed to attenuate kainate-mediated neurotoxicity. On the other hand, sigma/PCP, sigma and kappa-opioid ligands were potent inhibitors of hypoxia/hypoglycemia-induced neurotoxicity, although their neuroprotective potency did not correlate with their affinity for either the sigma or PCP binding sites. In conclusion, the ability of sigma and kappa-opioid ligands to attenuate hypoxia/hypoglycemia, but not NMDA or kainate-induced toxicity, suggests that these drugs exert their neuroprotective role by a predominantly presynaptic mechanism possibly by inhibiting ischemic-mediated glutamate release.
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PMID:Distinct neuroprotective profiles for sigma ligands against N-methyl-D-aspartate (NMDA), and hypoxia-mediated neurotoxicity in neuronal culture toxicity studies. 779 19

N-Methyl-D-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine-pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in MMDA-induced behaviors, CPP also failed to inhibit withdrawal jumping. Together these data indicated that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity.
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PMID:Increased N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid withdrawal. 785 Apr 59

We investigated the effect of the sigma selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that sigma sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at sigma sites, reverses the amnesia induced by a drug acting at the PCP site.
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PMID:PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice. 788 99

Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antagonists are toxic to neurons in the posterior cingulate and retrosplenial cortex. To determine if additional neurons are damaged, the distribution of microglial activation and 70 kDa heat shock protein (HSP70) induction was studied following the administration of PCP and MK801 to rats. PCP (10-50 mg/kg) induced microglial activation and neuronal HSP70 mRNA and protein expression in the posterior cingulate and retrosplenial cortex. In addition, coronal sections of the cerebellar vermis of PCP (50 mg/kg) treated rats contained vertical stripes of activated microglial in the molecular layer. In the sagittal plane, the microglial activation occurred in irregularly shaped patches, suggesting damage to Purkinje cells. In accord with this finding, PCP induced HSP70 protein and mRNA expression in Purkinje cells. Although there were relatively few foci of microglial activation and cells with HSP70 protein induction, HSP70 mRNA was detected in many Purkinje cells located throughout the cerebellar hemispheres as well as the vermis. MK801, at doses of 5-10 mg/kg, induced microglial activation and neuronal HSP70 mRNA and protein expression in the cingulate and retrosplenial cortex but not in the cerebellum. At the dose of 1 mg/kg MK801 induced HSP70 but did not consistently activate microglia. These data suggest that microglia are activated by MK801 doses that kill or severely damage neurons, whereas HSP70 is induced in "stressed" neurons at MK801 doses well below those that produce severe neurotoxicity. These observations suggest that PCP, but not MK801, is toxic to Purkinje cells and raise the question of whether NMDA antagonists or sigma ligands other than PCP are toxic to the cerebellum. Moreover, this study illustrates the usefulness of microglial activation and HSP70 induction as markers of neurotoxicity.
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PMID:Cerebellar toxicity of phencyclidine. 789 Nov 55


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