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)

The discriminative stimulus effects of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were investigated in animals trained to discriminate 1.5g/kg (pigeons) or 1.25g/kg (mice) ethanol from vehicle. Key-pecking of pigeons and lever responding of mice were maintained under fixed ratio schedules of mixed grain or milk reinforcement, respectively. Phencyclidine (PCP) and ketamine dose-dependently substituted for the ethanol stimulus in both species, with PCP being about 10-fold more potent than ketamine. In pigeons, PCP and ketamine fully substituted for ethanol at doses that did not significantly alter rates of responding; with mice, complete substitution was accompanied by response rate-decreasing effects. In pigeons, the highly selective NMDA receptor/ionophore antagonist MK-801 also substituted for ethanol at a dose that was accompanied by reduced response rates. Compounds that did not substitute for the ethanol stimulus were cocaine (both species), the 5-HT(1B) receptor agonist TFMPP (pigeon), the H(1) receptor antagonist hydroxyzine (mice), and the anticonconvulsants phenytoin and ethosuximide (mice). The present data show that PCP-like drugs that are antagonists of NMDA receptor-mediated neurotransmission share common discriminative stimulus effects with ethanol.
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PMID:Ethanol-like discriminative stimulus effects of non-competitive n-methyl-d-aspartate antagonists. 1122 52

Previous drug discrimination studies have elucidated the importance of the NMDA, GABA(A) and 5-HT(1) receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice drug discrimination paradigm in an attempt to determine whether the salient NMDA antagonistic effects were separable from other stimulus effects of ethanol. Adult Long-Evans rats (n = 7) were trained to discriminate ethanol (1.5g/kg, intragastric (i.g.)), the uncompetitive NMDA antagonist dizocilpine (0.17mg/kg, i.g.) or water (3.5ml, i.g.) under a food-reinforced fixed-ratio 15 (FR15) schedule of reinforcement. Following training, substitution tests were conducted with the GABA(A)/benzodiazepine (GABA(A)/BDZ) positive modulator pentobarbital (PB, 5.6-17mg/kg, i.g.), the uncompetitive NMDA antagonist phenycldine (PCP, 0.1-5.6mg/kg, i.p.) and the 5-HT(1) agonist RU 24969 (0.1-3.0mg/kg, i.p.). Complete substitution of PCP (ED(50), 0.9mg/kg) for dizocilpine was found in all animals. Conversely, PB (ED(50), 10mg/kg) substituted fully for ethanol in five of seven animals, whereas RU 24969 (ED(50), 1.4mg/kg) completely substituted for ethanol in only three of seven animals tested. The result demonstrate that a three-choice discrimination using dizocilpine, ethanol and water as training conditions can be established in rats. By contrasting the discriminative stimulus effects of an uncompetitive NMDA antagonist to ethanol, the ethanol-like effects of pentobarbital and RU 24969 are attenuated compared to previous studies of two-choice ethanol water discrimination.
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PMID:Assessment of the mixed discriminative stimulus effects of ethanol in a three-choice ethanol-dizocilpine-water discrimination in rats. 1122 67

5-HT and dopamine receptor antagonists have become widely used as atypical antipsychotics. Although 5-HT(2A) receptor antagonistic activity is thought to contribute to the atypical aspects of these agents, the precise mechanism remains unknown. M100907 (R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol), a selective 5-HT(2A) receptor antagonist, is reported to attenuate phencyclidine (PCP)-induced locomotion in rodents. For the purpose of identifying regions in which M100907 exerts its effect, we investigated the effects of M100907 on PCP-induced Fos expression in rat brain. PCP (5 mg/kg, subcutaneously, s.c.) induced Fos expression in the cingulate cortex area 3, the agranular insular cortex, the piriform cortex, the nucleus accumbens, the anterior paraventricular thalamic nucleus and the ventral lateral septal nucleus. Pretreatment with M100907 (0.5 mg/kg, s.c.) attenuated Fos expression induced by PCP in the nucleus accumbens core, the shell, the agranular insular cortex and the piriform cortex. M100907 did not induce Fos expression in any of the regions investigated including the dorsolateral caudate/putamen when given alone. These results indicate that 5-HT(2A) receptor antagonism attenuates Fos expression in a regionally specific manner in rat brain in the PCP model of psychosis.
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PMID:M100907, a selective 5-HT(2A) receptor antagonist, attenuates phencyclidine-induced Fos expression in discrete regions of rat brain. 1133 50

The 5-HT(6) receptor is targeted by several new antipsychotics such as clozapine, olanzapine, and sertindole. We studied the effect of SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide], a specific 5-HT(6) receptor antagonist, in three models for the positive symptoms of schizophrenia---D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI). We also tested this compound in a model for the negative symptoms of schizophrenia, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility, and to induce catalepsy in rats. The effect of SB-271046 was compared to clozapine in all models tested. This study showed that SB-271046 had no beneficial effect in PCP-disrupted SIT. However, SB-271046 dose-dependently normalised D-amphetamine-disrupted PPI, but did not reverse PCP-disrupted PPI. In addition, SB-271046 did not antagonise D-amphetamine-induced hyperactivity. Thus, this specific 5-HT(6) receptor antagonist was associated with a clear positive outcome in only one model for the positive symptoms of schizophrenia, and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy.
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PMID:Effects of the 5-HT(6) receptor antagonist, SB-271046, in animal models for schizophrenia. 1188 55

The 5-HT(7) receptor is targeted by several new antipsychotics such as clozapine and risperidone. We studied the effect of R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine (SB-258741), a specific 5-HT(7) receptor antagonist, in three models for positive symptoms, D-amphetamine-induced hyperactivity and D-amphetamine- and phencyclidine (PCP)-disrupted prepulse inhibition (PPI) in rats, with the aim of investigating the role of this receptor in the clinical effect of antipsychotics. We also tested this compound in a model for negative symptoms, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility and to induce catalepsy in rats. The effect of SB-258741 was compared to risperidone in all models. This study showed that SB-258741 had no beneficial effect on PCP-disrupted SIT. SB-258741 did not reverse D-amphetamine-disrupted PPI; however, it dose-dependently normalised PCP-disrupted PPI. SB-258741 antagonised D-amphetamine-induced hyperactivity but reduced motility of rats at similar doses. Thus, this specific 5-HT(7) receptor antagonist brought a clear positive outcome in only one model for positive symptoms of schizophrenia and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-258741 affects the PPI phenomenon but is not expected to have an antipsychotic effect on its own in clinic.
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PMID:Effects of the 5-HT(7) receptor antagonist SB-258741 in animal models for schizophrenia. 1188 57

Ketamine and PCP are commonly used as selective NMDA receptor antagonists to model the putative hypoglutamate state of schizophrenia and to test new antipsychotics. Recent findings question the NMDA receptor selectivity of these agents. To examine this further, we measured the affinity of ketamine and PCP for the high-affinity states of the dopamine D(2) and serotonin 5-HT(2) receptor and found that ketamine shows very similar affinity at the NMDA receptor and D(2) sites with a slightly lower affinity for 5-HT(2) (0.5 microM, 0.5 microM and 15 microM respectively), while PCP shows similar affinity for the NMDA and 5-HT(2) sites, with a slightly lower affinity for the D(2) site (2 microM, 5 microM and 37 microM respectively). Further, ketamine and PCP in clinically relevant doses caused a significant increase in the incorporation of [(35)S]GTP-gamma-S binding in CHO-cells expressing D(2) receptors, which was prevented by raclopride, suggesting a partial agonist effect at the D(2) receptor. Thus, ketamine and PCP may not produce a selective hypoglutamate state, but more likely produce a non-selective multi-system neurochemical perturbation via direct and indirect effects. These findings confound the inferences one can draw from the ketamine/PCP models of schizophrenia.
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PMID:NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. 1223 76

Recent studies have indicated that the selective group II metabotropic glutamate (mGlu) receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) shares common biochemical and pharmacological effects with the atypical antipsychotic clozapine. The present study aimed to further investigate these similarities (or differences) in monoamine-depleted animals by using the phencyclidine (PCP) model. Animals were pretreated 24 h before PCP administration with (i.p.) vehicle, alpha-methyl-DL-p-tyrosine methyl ester (alpha-MPT; 400 mg/kg), or DL-p-chlorophenyl-alanine methyl ester (PCPA; 300 mg/kg) injections. alpha-MPT and PCPA pretreatment significantly and selectively reduced catecholamine (dopamine and norepinepherine) or 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxyindoleacetic acid levels, respectively, in whole brain tissue. Both LY379268 and clozapine (s.c.) blocked PCP-evoked ambulatory activity and fine movements in control, alpha-MPT-, and PCPA-treated animals. In contrast, the typical antipsychotic haloperidol (s.c.) attenuated PCP behaviors in control and PCPA-pretreated animals, but was without effect in subjects pretreated with alpha-MPT. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate-selective antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)OH-tetrazole-6-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) attenuated locomotor activity in alpha-MPT-treated animals only, whereas the 5-HT(2A/2C)-selective antagonist ketanserin was effective at reducing ambulations and fine movements in control and alpha-MPT-treated animals. Taken together, these data indicate an important role for glutamatergic and serotonergic mechanisms for PCP-evoked behaviors in catecholamine-depleted animals and suggest that like clozapine, LY379268 is more effective than typical antipsychotics in these models. This study further supports the potential use of group II mGlu agonists as novel therapeutic agents in the treatment of schizophrenia.
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PMID:The group II metabotropic glutamate receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and clozapine reverse phencyclidine-induced behaviors in monoamine-depleted rats. 1243 10

The antipsychotic efficacy of AD-5423, which has the properties of both a serotonin 5-HT(2) and a dopamine D(2) receptor antagonist, was evaluated using animal models of schizophrenia. Sensitization to phencyclidine (PCP)-induced hyperlocomotion is considered a model of the positive symptoms of schizophrenia, and was significantly antagonized by AD-5423 and haloperidol. The PCP-induced enhancement of immobility induced by the forced swimming test, a model of the negative symptoms of schizophrenia, was attenuated by AD-5423 but not by haloperidol. Since this attenuated effect of AD-5423 was antagonized by DOI, a serotonin 5-HT(2) receptor agonist, it is postulated to be mediated by serotonin 5-HT(2) receptors. These findings suggest that AD-5423 would be clinically effective against both the positive and negative symptoms of schizophrenia.
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PMID:Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced behavioral changes in mice. 1259 44

The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC(50) values of 0.022 and 2.5 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D(1) and D(2) dopamine receptors, and 5-HT(1A) and 5-HT(2A) serotonin receptors in membranes prepared from rat brain or to cloned 5-HT(6) and 5-HT(7) receptors. At 10 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT(7) serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg i.p.) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg i.p.). Both NFPS and Org 24461 (1-10 mg/kg i.p.) reversed PCP-induced changes in EEG power spectra in conscious rats. These data support the view that GlyT1 inhibitors may have potential importance in treatment of negative symptoms of schizophrenia.
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PMID:The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study. 1266 95

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT(2A)/5-HT(2C)-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT(2)-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia-a clinical syndrome linked to enhanced sensitivity to N-methyl-d-aspartate (NMDA)-receptor antagonists.
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PMID:Effect of acute and chronic olanzapine treatment on phencyclidine-induced behavioral sensitization in rats with neonatal dopamine loss. 1515 33


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