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 effects of acute and chronic administration of phencyclidine (PCP) were examined in five male squirrel monkeys trained to respond on a chain fixed-interval fixed-ratio schedule of food presentation. Acute PCP (0.01-0.60) mg/kg i.m.) produced dose-related decreases in response rate during both components of the schedule. Both components were equally affected by the drug. The effects of the drug on fixed-interval response rate were dependent on the control rate of responding in corresponding segments of the interval. After the initial dose-response determination, the subjects were placed on an individualized regimen of chronic PCP administration lasting from 82 to 126 days, beginning with daily injections for 2 days alternating with saline injections for 2 days, progressing to four injections daily. No evidence of physical dependence was seen upon withdrawal of the drug. Redetermination of the dose-response function for PCP (0.03-1.0 mg/kg i.m.) demonstrated a nearly 2-fold shift to the right of both the fixed-interval and fixed-ratio dose-response curves, indicating tolerance. In addition, the subjects' behavior recovered sooner from a dose of PCP (0.60 mg/kg i.m.) given after the chronic regimen than from the same dose given before the chronic regimen. The results demonstrate that tolerance can occur to the behavioral effects of PCP in the squirrel monkey.
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PMID:The effects of acute and chronic phencyclidine on schedule-controlled behavior in the squirrel monkey. 41 49

Electrophilic and photoactivated agents have proven to be useful as receptor-selective irreversible probes. These compounds are generally derivatives of selected ligands that may be chemically modified in such a way as to retain high receptor affinity and selectivity while permitting covalent bonding to the receptor protein. The receptor systems described in this chapter are associated with a variety of classes of abused drugs. These irreversible agents are allowing the isolation and purification of these drug receptors to improve our understanding of their physiological and pharmacological properties and to aid us in better design of agents with therapeutic value without abuse or physical dependence liability. In the opioid field, beta-FNA and SUPERFIT have been successfully used to elucidate structure and function of the mu-, kappa-, and delta-receptors, respectively. Recently, the delta- and kappa-subtype selective irreversible ligands naltrindol and UPHIT have been introduced for receptor subtype studies that are designed to further clarify the physiological function of these sites. The PCP recognition site on the NMDA receptor complex and the sigma receptors have been characterized in part by the use of irreversible agents. These receptors, although sharing similar pharmacological properties, are clearly different systems and the irreversible agents described will allow their further characterization. The central-type benzodiazepine receptors have been labeled with irreversible agents; and, now, receptor subsites that differentially recognize beta-carbolines and benzodiazepines have been discovered through studies using a beta-carboline photoaffinity probe. The associated chloride ionophore has been studied with electrophilic irreversible ligands, as well as the pharmacologically distinct peripheral-type benzodiazepine receptors. Physiological function of the latter receptor system has been implicated through the photoaffinity ligand PK 14105, which is highly selective for these sites. Receptor subtype selective irreversible ligands also have been prepared for both the dopamine and sertonin receptors systems in hopes of clarifying their physiological roles in the CNS. It is clear that more selective irreversible compounds with higher affinity will continue to be in demand for further receptor characterization. In addition, radioligands with higher specific activity will continue to be important for molecular weight determination of receptor proteins and autoradiographic studies key to neuroanatomical localization of these sites.
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PMID:Irreversible ligands as probes for drug receptors. 166 79

Binding of [3H]spiperone to dopamine D2 receptors was measured in the striatum of male rats that were infused with phencyclidine (PCP, 45 mg/kg per day) or vehicle (saline) via an intrajugular cannula for 1, 3.5, or 7 days. The 7-day PCP infusion, which was shown previously to induce physical dependence, produced a significant 30% decrease in receptor density (Bmax). Two days after termination of the 7-day PCP infusion, Bmax values were no longer significantly lower than those of saline-infused controls. The acute administration of PCP (20 mg/kg, i.p.) did not alter receptor density 45 min later.
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PMID:[3H]Spiperone binding in the rat striatum during the development of physical dependence on phencyclidine and after withdrawal. 293 24

Chronic phencyclidine (PCP) administration has been shown to produce tolerance to a number of its pharmacological actions. We have suggested that PCP interacts with the 5-HT2 receptors since it inhibits [3H]spiperone binding to 5-HT2 receptors in vitro. In the present study, we investigated whether methysergide (a 5-HT2 receptor blocker) induces the precipitated withdrawal syndrome in PCP-tolerant rats. The body weight of the rats in the abrupt and precipitated withdrawal groups was significantly lower 5 days and 1-5 days after withdrawal, respectively, than that in the control group. Furthermore, other typical precipitated abstinence syndrome characteristics such as jumping, wet-dog shake and ptosis were also observed in the precipitated withdrawal group. These results suggest that PCP produces its behavioral effects via an agonistic interaction with 5-HT2 receptor sites and that our method may be very useful for the development of a rat model for studying physical dependence on PCP.
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PMID:Methysergide-induced precipitated withdrawal syndrome in phencyclidine-dependent rats. 376 58

The continuous infusion of 45 mg/kg/24 hr of phencyclidine (PCP) into the jugular vein of unrestrained rats induced tolerance to PCP-induced impairment of forced motor activity and physical dependence in 3.5 and 7 days, respectively. In drug-naive rats, an i.v. 2-mg/kg PCP test dose abolished rotarod performance for more than 20 min which returned to pretreatment values at 40 min. Eight hours after the termination of 3.5 days of infusion, rotarod performance of PCP-infused rats was significantly less impaired by the PCP test dose at 20 min than that of saline-infused controls. After infusion of PCP for 7 days, the duration of performance abolition produced by the PCP test dose (given 8 hr after the termination of infusion) was shortened further with performance significantly better than that of saline-infused controls at both 10 and 20 min. The results showed a greater than 2-fold tolerance development to this PCP effect and suggest the observed tolerance to be mainly functional in nature. Abrupt withdrawal of PCP after infusion for 7 days resulted in an abstinence syndrome with the following signs: piloerection, increased susceptibility to audiogenic seizures, transient weight loss and reductions in exploratory activity and rotarod performance. The first withdrawal signs were noted 4 hr after the termination of infusion. At 24 hr of abstinence, most of the withdrawal signs had subsided. The reduced rotarod performance, associated with withdrawal, could be reversed by a single i.v. dose of 2 mg/kg of PCP. The reversibility of this sign supports the interpretation of impaired rotarod performance after withdrawal as being an abstinence sign and adds to the experimental evidence that physical dependence on PCP is inducible within 7 days in rats.
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PMID:Continuous intravenous infusion of phencyclidine in unrestrained rats results in the rapid induction of tolerance and physical dependence. 404 May 69

Our present findings suggest that SKF-10,047, the prototype sigma agonist, has its opioid entity residing with its (-) isomer, while both its (+) and (-) isomers possess psychotogenic properties similar to those produced by PCP. We found that (-)-SKF-10,047 blocks EEG and behavioral effects of morphine in the naive rat, precipitates withdrawal in morphine-dependent rats, produces physical dependence as evidenced by naloxone-induced withdrawal, and displaces [3H]dihydromorphine from brain homogenates. (+)-SKF-10,047 did not produce dependence upon chronic treatment, and it did not displace [3H]dihydromorphine from brain homogenates. Such pharmacodynamic dissociation with SKF-10,047 suggests an association of sigma receptors with psychogenic, but not opioid effects. The latter are most likely mediated by mu or kappa receptors.
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PMID:Sigma receptors mediated the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties. 609 Sep 69

The repeated administration of phencyclidine (PCP, 72 mg/kg/day) to rats led to physical dependence, as evidenced by a withdrawal syndrome exhibited approx. 24-48 h following suspension of drug. All components of the withdrawal syndrome were suppressed by s.c. injections of PCP (16 mg/kg), (+/-)-N-allylnormetazocine (SKF-10047, 16 mg/kg) and (+)-SKF-10047 (16 mg/kg), but not by injections of saline or (-)-SKF-10047. Moreover, tolerance to the behavioral effects of PCP, as well as cross-tolerance to (+/-)-SKF-10047 and (+)-SKF-10047 were observed. These data indicate that PCP and the sigma opiate SKF-10047 share mechanisms of action, which are mediated by the (+)-isomer of the sigma agonist.
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PMID:Effects of SKF-10047 in the phencyclidine-dependent rat: evidence for common receptor mechanisms. 631 23

Studies on the effects of PCP have been conducted in volunteers in the Army Laboratories and elsewhere and in illicit users. The present review has summarized the observations of many investigators which showed that the acute effects of PCP following several routes of administration were shown to be dose-related. High doses of PCP produce disturbing manifestations including psychosis, numbness, light-headedness, vertigo, ataxia, and nystagmus due to acute intoxication. Furthermore, some subjects became irritable, argumentative or negative under the conditions of social stress and demanding tasks. In addition to a variety of central action, PCP has also been shown to affect cardiovascular function, heat storage, and exercise performance. PCP can also induce, although rarely, prolonged toxic psychosis in chronic abusers and precipitate psychotic episodes in psychotic and prepsychotic personalities. Tolerance, but not physical dependence, develops to the effects of PCP. Psychologic dependence as indicated by craving for the drug has however been reported.
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PMID:Phencyclidine (PCP): some human studies. 651 53

IV phencyclidine (PCP) self-administration was studied in five rhesus monkeys. The animals were given 23 h per day access with each respose producing an injection. For the first seven sessions saline was made contingent on responding. For the next 30 sessions responses produced 0.01 mg/kg PCP and for the next 20 sessions responses produced 0.05 mg/kg PCP. Withdrawal signs and symptoms were evaluated every 4 h during the subsequent saline-access period. All animals responded for 0.01 mg/kg injections at rates higher than their initial saline rates. Response rates decreased but total PCP intake increased during access to the higher dose. The levels of PCP self-administered resulted in severe intoxication. Evidence for physical dependence development was obtained. The symptoms emerged within 4--8 h after access was terminated, peaked at 12--16 h, and subsided by 24--48 h. The syndrome could be reversed by IV PCP administration. The most common symptoms were vocalizations, hyperresponsivity, bruxism, oculomotor hyperactivity, and diarrhea. During withdrawal the animals refused preferred food. In some of the animals piloerection, tremors, ear and facial twitches, and priapism occurred. Rhythmic abdominal contractions and emesis were seen in one subject and convulsive activity was seen in one subject.
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PMID:Continuous-access phencyclidine self-administration by rhesus monkeys leading to physical dependence. 677 35

Gammahydroxybutyrate (GHB) satisfies many of the criteria for consideration as a neuro-transmitter including having specific receptor sites, endogenous synthesis, and heterogeneous CNS distribution. GHB has been reported to be illicitly used, to induce physical dependence, and to relieve effects from alcohol and heroin withdrawal. GHB has also been shown to have antidopaminergic activity to displace 3H[MK-801] binding in brain membranes, and to have some in vivo effects similar to the typical antipsychotics. To characterize the behavioral pharmacology of GHB further, we evaluated it for its reinforcing effects upon IV administration in rhesus monkeys with PCP self-administration histories, its ability to produce heroin- and PCP-like discriminative stimulus effects, and for its ability to antagonize cocaine discrimination in rats. The results indicated that GHB (300-7500 micrograms/kg per infusion) was not self-administered above vehicle control rates, although self-infusions occurred at levels sufficient to produce signs indicative of sedation. Also, neither heroin nor PCP discriminative stimulus effects generalized to injections of GHB up to 300 mg/kg IP, and GHB did not effectively antagonize the cocaine discriminative stimulus when tested up to 300 mg/kg IP. These data indicate that GHB is unlike PCP as a reinforcer and that neither PCP nor heroin generalize to injections of GHB, nor can injections of GHB attenuate the discriminative stimulus effects of cocaine.
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PMID:Evaluation of the discriminative stimulus and reinforcing effects of gammahydroxybutyrate (GHB). 892 66


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