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)

In this study, we investigated whether risperidone, a serotonin-S2A (5-HT2A)/dopamine-D2 (D2)-receptor antagonist, inhibits phencyclidine (PCP)-induced stereotyped behaviors in comparison with haloperidol and ritanserin. Moreover, we also attempted to investigate the effects of these antipsychotics on the contents of dopamine, serotonin (5-HT) and their metabolites in rat striatum and frontal cortex. In rats, PCP (5 mg/kg, i.p.) caused hyperlocomotion and stereotyped behaviors, including sniffing, head-weaving, backpedalling and turning. Both resperidone (0.8-2.4 mg/kg, p.o.) and haloperidol (0.3-1.0 mg/kg, p.o.) inhibited these behaviors, except for backpedalling, in a dose-dependent manner. PCP (10 mg/kg, i.p.) produced hyperlocomotion and stereotyped behaviors, including rearing, sniffing head-twitch, backpedalling and turning. Risperidone (0.8-2.4 mg/kg, p.o.) inhibited both hyperlocomotion and PCP-induced behaviors, except for backpedalling, while ritanserin (3-10 mg/kg, p.o.) inhibited only the head-twitch. These results suggest that risperidone may have an antipsychotic effect on schizophrenia as well as PCP psychosis in humans by exerting a mixed 5-HT2A/D2 antagonism. Neurochemically, the increasing effects of risperidone on the content of DOPAC and the ratio of DOPAC to dopamine in the striatum were lower than those of haloperidol. These findings may support the view that the extrapyramidal side effects of risperidone are lower than those of haloperidol in clinical situations.
 ...
PMID:Effects of risperidone on phencyclidine-induced behaviors: comparison with haloperidol and ritanserin. 753 32

Whereas haloperidol more potently blocked the locomotion elicited by amphetamine (2.5 mg/kg i.p.) than that elicited by phencyclidine (PCP) (20.0 mg/kg s.c.), with inhibitory dose50s of 0.04 and 0.09 mg/kg s.c., respectively, clozapine more potently blocked the effect of PCP (0.04) than of amphetamine (8.8). Similarly, risperidone more potently blocked PCP (0.002) than amphetamine (0.2). In analogy to haloperidol, the selective dopamine D2 receptor antagonist, raclopride, antagonised amphetamine (0.16) more potently than PCP (0.8) whereas the selective 5-HT2A receptor antagonist, [R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol] (MDL 100,907), only antagonised PCP (0.001) as compared to amphetamine (> 10.0). The potency for inhibition of PCP correlated more highly to affinity at 5-HT2A (r = 0.97, P < 0.01) than dopamine D2 (0.57, P > 0.05) sites, while the potency for blockade of amphetamine correlated more highly with affinity at dopamine D2 (0.94, P < 0.01) than at 5-HT2A sites (0.37, P > 0.05). In conclusion, in contrast to amphetamine, induction of locomotion by PCP is dependent upon functional 5-HT2A receptors, antagonism of which by 'atypical' antipsychotics underlies their ability to inhibit PCP-induced locomotion.
 ...
PMID:Blockade of phencyclidine-induced hyperlocomotion by clozapine and MDL 100,907 in rats reflects antagonism of 5-HT2A receptors. 758 72

We used in vitro quantitative autoradiography to investigate changes in neurotransmitter receptor binding, including muscarinic cholinergic, PCP, GABAA, benzodiazepine, D1 and 5-HT2A receptor, in the brains of aged rats, compared with such binding in young rats. Scatchard analysis revealed that the maximal number of binding sites for [3H]quinuclidinyl benzilate (QNB) in the caudate/putamen and accumbens was significantly decreased in aged rats compared with young rats, while its affinity remained unchanged. The specific binding of [3H]N-(1-[2-thienyl]cyclohexyl)3,4-piperidine (TCP) for the ion channels coupled with N-methyl-D-aspartate receptors in the caudate/putamen and hippocampus was significantly decreased in aged rats compared with young rats. The [3H]muscimol binding in aged rats was decreased in all brain regions examined compared with that in young rats, whereas [3H]flunitrazepam binding was not changed in any brain regions. The [3H]SCH23390 binding for dopamine D1 receptors was significantly increased in the parietal cortex, but decreased in the caudate/putamen and accumbens of aged rats compared with that in young rats. The [3H]ketanserin binding for 5-HT2A receptors in the cortex and accumbens was significantly decreased in aged rats compared with young rats. These results suggest that uneven changes in receptors for various neurotransmitters throughout the brain may be responsible for the decline of brain function in aged rats.
 ...
PMID:Changes in muscarinic cholinergic, PCP, GABAA, D1, and 5-HT2A receptor binding, but not in benzodiazepine receptor binding in the brains of aged rats. 796 30

1. Immobility induced by forced swimming is well known as an animal model of depression. To develop an animal model for the negative symptoms of schizophrenia, in particular the depressive symptoms, the effect of phencyclidine (PCP) on immobility in the forced swimming test was investigated in mice, since PCP produces such negative symptoms in humans. 2. Repeated treatment with PCP (10 mg kg-1 day-1, s.c., once a day for 14 days) prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment; the effect was not obtained by single or 5 treatments with PCP (10 mg kg-1, s.c.), or by repeated treatment with methamphetamine (0.5 and 1 mg kg-1 day-1, s.c., once a day for 14 days). 3. The enhancing effect of PCP (10 mg kg-1 day-1, s.c.) on the immobility persisted for at least 21 days after the withdrawal of the drug. 4. Haloperidol (0.3 and 1 mg kg-1, p.o.), ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.1-1 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.) failed to attenuate the immobility induced by the forced swimming in mice repeatedly treated with saline when the drugs were administered 1 h before the forced swimming test. However, ritanserin (30 mg kg-1) and clozapine (30 mg kg-1) did attenuate this immobility. 5. The enhancing effect of PCP on the immobility was attenuated by ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.3 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.), whereas haloperidol (0.3 and 1 mg kg-1, p.o.) had no effect. 6. These results suggest that the enhancement of immobility in the forced swimming test brought about by repeated PCP treatment could be used as a model of the negative symptoms, particularly the depression, of schizophrenia. This effect of PCP appeared to be mediated, at least in part, via 5-HT2A receptors.
 ...
PMID:Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. 858 Dec 95

The open channel N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine (MK-801) and phencyclidine (PCP) increase the firing rate of both A9 and A10 dopaminergic neurons in the rat. In the A10 nucleus, this effect of MK-801 is reportedly prevented by either competitive NMDA antagonists or serotonin2 (5-HT2) antagonists. The present study examined the neurochemical correlates of these effects using the technique of in vivo microdialysis in conscious rats. In contrast to its reported electrophysiological effects at the cell body level, MK-801 (2 mg/kg, i.p.) has divergent effects on dopamine release in the terminal fields of the A9 and A10 systems. MK-801 stimulated dopamine release in both the medial prefrontal cortex and the nucleus accumbens but tended to decrease release in the striatum. Stimulated dopamine release in the nucleus accumbens was selectively blocked by either the competitive NMDA receptor antagonist, MDL 100,453 or the 5-HT2A receptor antagonist, MDL 100,907. Neither MDL 100,453 nor MDL 100,907 affected MK-801-induced release in the medial prefrontal cortex. The results illustrate the complex regulation of the forebrain dopaminergic systems by glutamate and indicate that the serotonergic system, via the 5-HT2A receptor, may play an important role in this regulation.
 ...
PMID:Regional effects of MK-801 on dopamine release: effects of competitive NMDA or 5-HT2A receptor blockade. 866 21

To analyze the mechanisms of PCP abuse, we investigated the changes in PCP-induced motivational properties and neuronal functions in animals. First, we determined that PCP-induced withdrawal syndrome may, in part, be produced by 5-HTergic neuronal systems. Second, using rats treated with subacute PCP, we established that subacute PCP may produce behavioral changes (stereotyped behaviors and hyperlocomotion), mediated by both dopaminergic, 5-HTergic neuronal, and NO systems. Third, using the place conditioning paradigm, we confirmed that (1) both dopamine-D1 and 5-HT2A receptors, but not sigma receptors, may be involved in PCP-induced place aversion, and (2) subacute PCP produces place preference. Finally, we demonstrated that subacute PCP may produce neurochemical changes (the number of 5-HT2A receptors, dopamine turnover, NO synthesis, and immediate early gene expression). These results suggested that several neuronal changes may be related to behavioral changes induced by subacute PCP. Furthermore, it is hypothesized that the alternations of several neuronal systems may establish PCP abuse via the changes of the immediate early gene expression and NO activity induced by subacute PCP treatment. Further studies using receptor selective ligands and sensitive probes that could associate with the pharmacological actions of PCP may elucidate the mechanisms of PCP abuse.
 ...
PMID:Functional changes in neuronal systems induced by phencyclidine administration. 895 21

In humans, phencyclidine (PCP) is known to produce a syndrome of behavioral effects which have many characteristics in common with schizophrenia. Therefore, antagonism of PCP effects might be evidence for antipsychotic efficacy of a compound. In the present studies, the effects of the D2-like antagonist haloperidol, the mixed D2-like/5-HT2 antagonists olanzapine and clozapine, and a series of 5-HT receptor subtype selective antagonists on the hyperlocomotion produced by PCP were evaluated in mice. PCP (0.3-10 mg/kg) produced a dose-related increase in locomotor activity, with a peak effect at 3.0 mg/kg. The D2-like antagonist haloperidol produced a dose-related decrease in locomotor activity when administered alone, and blocked the hyperactivity effects of PCP over the same dose-range (minimal effective dose, MED = 0.3 mg/kg for both effects). In contrast, olanzapine and clozapine reversed the hyperlocomotion effects of PCP at doses (MED = 0.03 and 0.3 mg/kg, respectively) approximately 30- and 10-fold, respectively, below those that decreased activity when administered alone (MED = 1.0 and 3.0 mg/kg, respectively). The selective 5-HT2 antagonist LY53857 (0.3-3.0 mg/kg) administered alone had no effect on locomotor activity but reversed (MED = 0.1 mg/kg) the effects of PCP. Similarly, the selective 5-HT2A/2C antagonist ritanserin (0.001-1.0 mg/kg) alone had no effect on locomotor activity, but reversed (MED = 0.01 mg/kg) the effects of PCP. The selective 5-HT2A antagonists ketanserin (MED = 3.0 mg/kg) and MDL 100,907 (MED = 0.3 mg/kg) produced dose-related decreases in locomotor activity and ketanserin (MED = 0.1 mg/kg) and MDL 100,907 (MED = 0.003 mg/kg) reversed the effects of PCP. The selective 5-HT3 antagonist zatosetron (0.01-10 mg/kg) and the selective 5-HT1A antagonist WAY 100,635 (0.001-3 mg/kg) were without effects on spontaneous locomotor activity. Zatosetron reversed the effects of 3.0 mg/kg PCP at the nonselective dose of 10 mg/kg whereas WAY 100,635 (0.001-1 mg/kg) did not affect PCP-induced hyperlocomotion. The present results indicate that PCP increases locomotor activity, at least in part, due to actions at 5-HT2A, but not 5-HT3 or 5-HT1A, receptors. Further, the present findings support the hypothesis that antagonism at 5-HT2A receptors contributes to the in vivo actions of atypical antipsychotics such as olanzapine and clozapine.
 ...
PMID:Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. 912 67

In the present study, we demonstrate that, in a concentration-dependent manner, M100907 (formerly MDL 100907, a highly selective 5-HT2A receptor antagonist and a purported atypical antipsychotic drug [APD]), but not its much less active stereoisomer M100009, completely prevents or markedly reverses the phencyclidine (PCP)-induced blockade of N-methyl-D-aspartate (NMDA) responses in pyramidal neurons of the medial prefrontal cortex (mPFC). Furthermore, the atypical APD clozapine, but not the typical APD haloperidol or raclopride (a selective dopamine D2,3 receptor antagonist), mimicked the action of M100907, preventing the PCP-induced effect. These results suggest that M100907 might be an antidote for treating the PCP-induced psychotomimetic state that closely resembles schizophrenia; they could also account for the antipsychotic potential of M100907. Furthermore, our results suggest that the prototype (clozapine) and a candidate (M100907) atypical APDs might be effective in ameliorating schizophrenic symptoms including cognitive and neuropsychological deficits, which are induced in humans who abuse PCP. We hypothesize that the ability of M100907 and clozapine to prevent or reverse the PCP-induced blockade of the NMDA receptor channel is attributed to their 5-HT2A receptors antagonizing property. Therefore, with further systematic studies, the ability of compounds to prevent or reverse PCP's blockade of NMDA responses may prove to be an effective electrophysiological model for screening potential atypical APDs and predicting their therapeutic efficacy in cognitive deficits.
 ...
PMID:M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortical slice. 960 79

Schizophrenic and schizotypal patients exhibit deficits in the habituation and prepulse inhibition (PPI) of startle responses, providing operational measures of the sensorimotor gating or filtering deficits suggested to contribute to cognitive disorganization in these patients. In rats, hallucinogens, entactogens, and NMDA antagonists share the ability to both retard startle habituation and disrupt PPI. Extensive pharmacological studies in rats have indicated that the effects of hallucinogens on habituation are mediated by direct agonist actions at 5-HT2 receptors. The effects of the entactogens on both habituation and PPI reflect indirect agonist actions due to the stimulation of presynaptic serotonin release. These observations in rats have supported the development of 5-HT2A antagonists for the treatment of schizophrenia. Animal studies have shown that PPI is modulated by multiple interacting neurotransmitters, including dopaminergic, serotonergic, cholinergic, GABAergic, and glutamatergic systems within cortical, limbic, striatal, and brainstem structures. The effects of PCP and other NMDA antagonists on PPI are insensitive to either dopaminergic or serotonergic antagonists, but are reduced by atypical antipsychotics such as clozapine, olanzapine, and Seroquel. Thus, the PCP model of schizophrenia-like deficits in sensorimotor gating offers promise for the identification and neurobiological investigation of atypical antipsychotics. The cross-species study of homologous gating functions, such as habituation and PPI, in animal models and psychiatric patients provides novel opportunities for the exploration of neurobiological substrates relevant to the group of schizophrenias.
 ...
PMID:Behavioral studies of hallucinogenic drugs in animals: implications for schizophrenia research. 975 37

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains.
 ...
PMID:M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. 1008 32


1 2 3 Next >>