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)

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

Long-Evans hooded rats were initially trained to lever press, in standard, operant conditioning chambers, according to a fixed-ratio 1 (FR1) reinforcement schedule using 0.06ml deliveries of 8% w/v ethanol as the reinforcer, during daily Monday-Friday, 1h experimental sessions. Next, experimental sessions were reduced to 0.5h, the FR value was increased to 5, and the rats were trained to discriminate 2.0mg/kg s.c. phencyclidine (PCP) from saline vehicle using standard, drug discrimination training procedures, with 8% ethanol as the reinforcer. Following training, dose-response tests with PCP (0.1-4.0mg/kg), ketamine (0.1-18mg/kg), dexoxadrol (1.0-5.6mg/kg) and morphine (1.0-9.0mg/kg) were conducted. More PCP-lever presses were emitted than saline-lever presses at several doses of PCP, ketamine, and dexoxadrol, indicating generalization from the 2.0mg/kg PCP stimulus. When morphine was tested, more saline-lever than PCP-lever presses were made, and percent PCP-lever pressing never exceeded an average of 12% at any dose tested. This study demonstrates that one drug of abuse, PCP, can serve as a discriminative stimulus when another drug of abuse, ethanol, serves as the reinforcing stimulus, and is the first explicit laboratory demonstration of drug discriminative stimulus control during drug self-administration.
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PMID:Phencyclidine established as a discriminative stimulus using ethanol as a reinforcer. 1122 52

The non-competitive N-methyl-D-aspartate (NMDA) antagonists MK-801, PCP and ketamine have recently been found to produce full drug-appropriate responding in pigeons trained to ethanol (1.5g/kg) in a two-key operant drug discrimination procedure. In the present study, ethanol (0.56-3.2g/kg i.g.) was administered to pigeons trained to discriminate MK-801 (0.18mg/kg, n = 5), PCP (1.0mg/kg, n = 4) or the competitive NMDA antagonist CGS-19755 (1.8mg/kg, n = 4) from vehicle. Up to doses that caused large reductions in response rates, ethanol produced only vehicle-appropriate responding in the pigeons trained to PCP and only low levels of drug-appropriate responding in pigeons trained to MK-801 and CGS-19755. The present results suggest there could be asymmetric generalization between the discriminative stimulus effects of i.g. ethanol and NMDA antagonists.
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PMID:Ethanol effects in pigeons trained to discriminate MK-801, PCP or CGS-19755. 1122 71

The acute effects of ethanol (EtOH) on fixed-ratio performance were studied in separate lines of mice selectively bred for differences in severity of handling-induced convulsions following withdrawal from EtOH. Because modulation of N methyl-D-aspartate (NMDA) receptors has been implicated in production of the acute and withdrawal-induced effects of EtOH, we also tested NMDA and three NMDA antagonists. Withdrawal seizure-resistant (WSR2) mice were more sensitive to the response rate-decreasing effects of EtOH than were withdrawal seizure-prone (WSP2) mice. Similar to EtOH, NPC 12626 (a competitive NMDA antagonist) and phencyclidine (a non-competitive NMDA antagonist) decreased responding in WSR2 mice at doses that did not affect responding in WSP2 mice. Although a second non-competitive NMDA antagonist, dizocilpine, produced line differences in the same direction as did PCP, these differences were not statistically significant. In contrast, NMDA produced nearly equipotent dose-dependent response rate decreases in both lines. Combined with the results of previous in vitro studies which showed that the number of NMDA receptors in the hippocampi of WSR2 and WSP2 mice differ, the results of the present study suggest that the interaction of EtOH with NMDA receptors may contribute to differences in the acute effects of ethanol on schedule-controlled behavior in WSP2 and WSR2 mice.
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PMID:Effects of ethanol and NMDA antagonists on operant behavior in ethanol withdrawal seizure-prone and-resistant mice. 1122 77

Both enhancement of GABAergic neurotransmission and antagonism of glutamatergic neurotransmission involving the NMDA receptor have been implicated in the acute effects of ethanol. In this study, rats were trained to discriminate 1000mg/kg ethanol from saline. This dose of ethanol was consistently discriminated from saline but had no effects on overall rates of responding. Substitution tests were conducted with a number of GABA agonists and NMDA antagonists. Both midazolam and pentobarbital exhibited substantial substitution for ethanol at doses that moderately decreased response rates. However, muscimol and baclofen completely failed to substitute for ethanol, as did a combination of a fixed dose of muscimol with increasing doses of baclofen. The non-competitive NMDA antagonists PCP, dizocilpine and ketamine substituted fully for ethanol, but only at doses that also substantially suppressed rates of responding. The competitive NMDA antagonists, CPPene and NPC 17742, partially substituted for ethanol. The levels of substitution for ethanol among the indirect GABA agonists and the non-competitive NMDA antagonists indicate that the discriminative stimulus effects of ethanol, at least at a 1000mg/kg dose, may involve both GABAergic and glutamatergic systems.
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PMID:Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. 1122 96

Two novel quinoxalinedione glutamatergic antagonists, with in vitro selectivity for the glycine modulatory site on the N-methyl-d-aspartate (NMDA) receptor, were evaluated in a number of behavioral tests primarily designed to compare their effects to those of the noncompetitive NMDA antagonist phencyclidine (PCP). The compounds evaluated were 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) and 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021). In rats, both ACEA-1011 and ACEA-1021 were completely devoid of PCP-like discriminative stimulus effects, although behavioral activity, in the form of response rate suppression, was seen at the higher doses tested (6-25mg/kg, i.p.). ACEA-1011 and ACEA-1021 were also ineffective as antagonists of PCP discrimination in rats. ACEA-1021 failed to substitute in rhesus monkeys trained to discriminate PCP from sham injection, although in the monkeys minimal effects were observed on rates of responding even at the highest dose tested (10.2mg/kg, i.v.). ACEA-1021 also failed to produce ethanol-like discriminative stimulus effects in rats under test conditions where PCP has been shown to produce substantial levels of substitution for ethanol. Both ACEA-1011 and ACEA-1021 were also evaluated as antagonists of NMDA discrimination in rats. ACEA-1011 produced some decreases in NMDA-lever responding, with the largest effect at one intermediate dose (3mg/kg, i.p.). ACEA-1021 was ineffective as an antagonist of NMDA discrimination. Unlike results reported for PCP-like NMDA antagonists, neither ACEA-1011 nor ACEA-1021 disrupted prepulse inhibition of the acoustic startle reflex in rats. It was not possible to establish ACEA-1021 (10 or 15.6mg/kg) as a discriminative stimulus in rats. In conclusion, the novel glutamate antagonists ACEA-1011 and ACEA-1021 did not produce a profile of behavioral effects similar to that of PCP-like noncompetitive NMDA antagonists. These results are consistent with an emerging body of evidence showing differences in the behavioral effects of different classes of glutamate antagonists.
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PMID:Behavioral pharmacology of two novel substituted quinoxalinedione glutamate antagonists. 1122 65

In each of different groups of rats trained to discriminate either 8-OH-DPAT, DOI, d-amphetamine, cocaine, chlordiazepoide or ethanol from saline, dizocilpine produced maximum percentages of drug lever (DL) selection that were intermediate between those produced by the training conditions. Dizocilpine also decreased DL selection produced by the training dose in each of the discriminations, except in ethanol-trained rats. In all discriminations, with the exception of ethanol-trained rats, the intermediate levels of DL, selection produced by dizocilpine were associated with increased FRF values (sum of the responses made on either lever before the first reinforcement occurred), increased lever selection latencies, and increased responding on the nonselected lever. At doses that, in general, had effects on response rate similar to those of dizocilpine, intermediate levels of DL selection were produced by BMY 7378 in 8-OH-DPAT-trained rats, by WY 50,324 in DOI-trained rats, by (-)-3-PPP in d-amphetamine- and in cocaine-trained rats, by alpidem in chlordiazepoxide-trained rats, and by PCP in ethanol-trained rats. The intermediate levels of DL selection produced by these latter drugs were not associated with simultaneous increases of FRF values, selection latencies, and responding on the nonselected lever. The results suggest that dizocilpine produces intermediate levels of drug-appropriate responding through the behavioral mechanism of partial generalization only in ethanol-trained rats; in all other discriminations examined here, the effects of dizocilpine appear to involve (1) pharmacological effects that differ from those of the training drug, and (2) behavioral mechanisms that are unrelated to stimulus generalization. The differentiation of partial generalization and other mechanisms whereby intermediate responding can occur in the drug discrimination paradigm requires analyses that are more detailed than those commonly used in drug discrimination research.
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PMID:Effects of the NMDA antagonist, dizocilpine, in various drug discriminations: characterization of intermediate levels of drug lever selection. 1122 66

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

There is increasing evidence that kappa-opioid receptor agonists modulate cocaine-maintained behavior, and limited findings implicate the involvement of kappa-opioid receptors in ethanol-maintained behaviors. The purpose of the present study was to investigate the effects of bremazocine, a kappa-opioid agonist, on the self-administration of smoked cocaine base and oral ethanol in rhesus monkeys (Macaca mulatta). To determine the selectivity of bremazocine, the effects of bremazocine pretreatment on the oral self-administration of phencyclidine (PCP), saccharin, and food were also examined. Adult male rhesus monkeys were trained to self-administer oral ethanol, PCP, saccharin (n = 8), food (n = 6), or smoked cocaine base (n = 6) and water during daily sessions. Bremazocine (0.00032-, 0.001-, and 0.0025-mg/kg i.m.) injections were given 15 min before session. The 4 days of stable behavior before pretreatment served as baseline. Demand curves (consumption x fixed ratio; FR) were obtained for smoked cocaine base, ethanol, and PCP by varying the cost (FR) of drug deliveries and measuring consumption (deliveries). Bremazocine (0.001 mg/kg) was administered at each FR value in nonsystematic order. Results indicate that bremazocine dose dependently reduced cocaine, ethanol, PCP, and saccharin intake. Food intake was affected less by bremazocine than the other substances in five of the six monkeys. Generally, bremazocine treatment reduced the demand for cocaine, ethanol, and PCP as well as other measures of response strength. These results extend the findings that kappa-agonists reduce the self-administration of drug and nondrug reinforcers to smoked cocaine base and oral ethanol, PCP, and saccharin in rhesus monkeys.
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PMID:Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis. 1202 30

Here, I will review accumulating evidence that during the developmental period of synaptogenesis, also known as the brain growth spurt period, neurons are very sensitive to specific disturbances in their synaptic environment. During this period, abnormal increases in NMDA glutamate (Glu) receptor activity triggers excitotoxic neurodegeneration, and abnormal inhibition of neuronal activity (by blockade of NMDA Glu receptors or excessive activation of GABAA receptors) triggers neuronal suicide (apoptosis). Only a transient disturbance, lasting for a few hours, is sufficient to trigger either excitotoxic or apoptotic neurodegeneration during this developmental period. Ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers widespread apoptotic neurodegeneration in the developing rat, mouse or guinea pig brain, and this provides a likely explanation for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The brain growth spurt occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the 6th month of gestation to several years after birth. Thus, there is a period in fetal and neonatal human development, lasting for several years, during which immature central nervous system (CNS) neurons are exquisitely sensitive to environmental agents (the specific number and variety of which remains to be established) that can trigger widespread neurodegeneration by inducing specific abnormal changes in the synaptic environment. Agents identified thus far include drugs that may be abused by pregnant mothers (ethanol, phencyclidine (PCP) (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines) and many medicinals used in obstetric and pediatric medicine as sedatives, anti-convulsants or anesthetics (all general anesthetics are either NMDA antagonists or GABAmimetics). Many other chemicals in the human environment remain to be evaluated for their ability to cause developing CNS neurons to commit suicide, and this provides an exciting challenge for the field of developmental neurotoxicology.
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PMID:New insights and new issues in developmental neurotoxicology. 1252 Jul 55


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