Social stimuli enhance phencyclidine (PCP) self-administration in rhesus monkeys

PubMed Central

Newman, Jennifer L.; Perry, Jennifer L.; Carroll, Marilyn E.

2007-01-01

Environmental factors, including social interaction, can alter the effects of drugs of abuse on behavior. The present study was conducted to examine the effects of social stimuli on oral phencyclidine (PCP) self-administration by rhesus monkeys. Ten adult rhesus monkeys (M. mulatta) were housed side by side in modular cages that could be configured to provide visual, auditory, and olfactory stimuli provided by another monkey located in the other side of the paired unit. During the first experiment, monkeys self-administered PCP (0.25 mg/ml) and water under concurrent fixed ratio (FR) 16 schedules of reinforcement with either a solid or a grid (social) partition separating each pair of monkeys. In the second experiment, a PCP concentration-response relationship was determined under concurrent progressive ratio (PR) schedules of reinforcement under the solid and grid partition conditions. Under the concurrent FR 16 schedules, PCP and water self-administration was significantly higher during exposure to a cage mate through a grid partition than when a solid partition separated the monkeys. The relative reinforcing strength of PCP, as measured by PR break points, was greater during the grid partition condition compared to the solid partition condition indicated by an upward shift in the concentration-response curve. To determine whether the social stimuli provided by another monkey led to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which may have evoked the increase of PCP self-administration during the grid partition condition, a third experiment was conducted to examine cortisol levels under the two housing conditions. A modest, but nonsignificant increase in cortisol levels was found upon switching from the solid to the grid partition condition. The results suggest that social stimulation among monkeys in adjoining cages leads to enhanced reinforcing strength of PCP. PMID:17560636

The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via σ1 receptor activation: comparison with the effects of dextromethorphan

PubMed Central

Shin, Eun-Joo; Nah, Seung-Yeol; Kim, Won-Ki; Ko, Kwang Ho; Jhoo, Wang-Kee; Lim, Yong-Kwang; Cha, Joo Young; Chen, Chieh-Fu; Kim, Hyoung-Chun

2005-01-01

In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at σ1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg−1, i.p.) produced robust convulsions lasting 4–6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg−1) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective σ1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to σ1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. PMID:15723099

Effects of acute phencyclidine administration on arginine metabolism in the hippocampus and prefrontal cortex in rats.

PubMed

Knox, Logan T; Jing, Yu; Collie, Nicola D; Zhang, Hu; Liu, Ping

2014-06-01

Phencyclidine (PCP), a non-competitive N-methyl-d-aspartate glutamate receptor antagonist, induces schizophrenic symptoms in healthy individuals, and altered arginine metabolism has been implicated in schizophrenia. The present study investigated the effects of a single subcutaneous injection of PCP (2, 5 or 10 mg/kg) on arginine metabolism in the sub-regions of the hippocampus and prefrontal cortex in male young adult Sprague-Dawley rats. Animals' general behaviour was assessed in the open field apparatus 30 min after the treatment, and the brain tissues were collected at the time point of 60 min post-treatment. Behaviourally, PCP resulted in reduced exploratory activity in a dose-dependent manner, and severe stereotype behaviour and ataxia at the highest dose. Neurochemically, PCP significantly altered the nitric oxide synthase and arginase activities, the l-arginine, agmatine, spermine, glutamate and GABA levels, and the glutamine/glutamate and glutamate/GABA ratios in a dose-dependent and/or region-specific manner. Cluster analyses showed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which changed as a function of PCP mainly in the hippocampus. Multiple regression analysis revealed significant neurochemical-behavioural correlations. These results demonstrate, for the first time, that a single acute administration of PCP affects animals' behaviour and arginine metabolism in the brain. Copyright © 2014 Elsevier Ltd. All rights reserved.

Taming the ketamine tiger. 1965.

PubMed

Domino, Edward F

2010-09-01

Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were determined in 20 volunteers from a prison population. The results indicate that this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0 mg per kilogram. With intravenous administration the onset of action is within 1 min and the effects last for about 5 to 10 min, depending on dosage level and individual variation. No tachyphylaxis was evident on repeat doses. Respiratory depression was slight and transient. Hypertension, tachycardia, and psychic changes are undesirable characteristics of the drug. Whether these can be modified by preanesthetic medication was not determined in this study. Recovery from analgesia and coma usually took place within 10 min, although from electroencephalographic evidence it may be assumed that subjects were not completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity was obtained. CI-581 produces pharmacologic effects similar to those reported for phencyclidine, but of shorter duration. The drug deserves further pharmacologic and clinical trials. It is proposed that the words "dissociative anesthetic" be used to describe the mental state produced by this drug.

Essential Role of NMDA Receptor Channel ε4 Subunit (GluN2D) in the Effects of Phencyclidine, but Not Methamphetamine

PubMed Central

Hagino, Yoko; Kasai, Shinya; Han, Wenhua; Yamamoto, Hideko; Nabeshima, Toshitaka; Mishina, Masayoshi; Ikeda, Kazutaka

2010-01-01

Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DAex) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DAex in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4. PMID:21060893

Ketamine and phencyclidine: the good, the bad and the unexpected

PubMed Central

Lodge, D; Mercier, M S

2015-01-01

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. PMID:26075331

Two Cases of Non-fatal Intoxication with a Novel Street Hallucinogen: 3-Methoxy-Phencyclidine.

PubMed

Zidkova, Monika; Hlozek, Tomas; Balik, Martin; Kopecky, Ondrej; Tesinsky, Pavel; Svanda, Jan; Balikova, Marie Anna

2017-05-01

3-Methoxy-phencyclidine (3-MeO-PCP) is a structural derivative of the dissociative hallucinogen phencyclidine (PCP). Although PCP toxicity is well documented, little is known about this new psychoactive substance despite being available on the black market even in central Europe. The objective of this case report is to present clinical and laboratory data of analytically confirmed non-fatal intoxication of two subjects with 3-MeO-PCP. A preliminary assessment of potential metabolites excreted into urine was enabled using the liquid chromatography high resolution mass spectrometric method. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized (1)H MRS study.

PubMed

Iltis, Isabelle; Koski, Dee M; Eberly, Lynn E; Nelson, Christopher D; Deelchand, Dinesh K; Valette, Julien; Ugurbil, Kamil; Lim, Kelvin O; Henry, Pierre-Gilles

2009-08-01

Acute phencyclidine (PCP) administration mimics some aspects of schizophrenia in rats, such as behavioral alterations, increased dopaminergic activity and prefrontal cortex dysfunction. In this study, we used single-voxel (1)H-MRS to investigate neurochemical changes in rat prefrontal cortex in vivo before and after an acute injection of PCP. A short-echo time sequence (STEAM) was used to acquire spectra in a 32-microL voxel positioned in the prefrontal cortex area of 12 rats anesthetized with isoflurane. Data were acquired for 30 min before and for 140 min after a bolus of PCP (10 mg/kg, n = 6) or saline (n = 6). Metabolites were quantified with the LCModel. Time courses for 14 metabolites were obtained with a temporal resolution of 10 min. The glutamine/glutamate ratio was significantly increased after PCP injection (p < 0.0001, pre- vs. post-injection), while the total concentration of these two metabolites remained constant. Glucose was transiently increased (+70%) while lactate decreased after the injection (both p < 0.0001). Lactate, but not glucose and glutamine, returned to baseline levels after 140 min. These results show that an acute injection of PCP leads to changes in glutamate and glutamine concentrations, similar to what has been observed in schizophrenic patients, and after ketamine administration in humans. MRS studies of this pharmacological rat model may be useful for assessing the effects of potential anti-psychotic drugs in vivo. 2009 John Wiley & Sons, Ltd.

Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia.

PubMed

Santini, Martin A; Ratner, Cecilia; Aznar, Susana; Klein, Anders B; Knudsen, Gitte M; Mikkelsen, Jens D

2013-05-01

Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (Arc), c-fos, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.

PubMed

Mattsson, Anna; Lindqvist, Eva; Ogren, Sven Ove; Olson, Lars

2005-11-07

Altered cholinergic function is considered as a potential contributing factor in the pathogenesis of schizophrenia. We hypothesize that cortical cholinergic denervation may result in changes in glutamatergic activity. Therefore, we lesioned the cholinergic corticopetal projections by local infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of rats. Possible effects of this lesion on glutamatergic systems were examined by phencyclidine-induced locomotor activity, and also by N-methyl-D-aspartate receptor binding. We find that cholinergic lesioning of neocortex leads to enhanced sensitivity to phencyclidine in the form of a dramatic increase in horizontal activity. Further, N-methyl-D-aspartate receptor binding is unaffected in denervated rats. These results suggest that aberrations in cholinergic function might lead to glutamatergic dysfunctions, which might be of relevance for the pathophysiology for schizophrenia.

Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice

PubMed Central

Barzilay, R; Ben-Zur, T; Sadan, O; Bren, Z; Taler, M; Lev, N; Tarasenko, I; Uzan, R; Gil-Ad, I; Melamed, E; Weizman, A; Offen, D

2011-01-01

Stem cell-based regenerative therapy is considered a promising cellular therapeutic approach for the patients with incurable brain diseases. Mesenchymal stem cells (MSCs) represent an attractive cell source for regenerative medicine strategies for the treatment of the diseased brain. Previous studies have shown that these cells improve behavioral deficits in animal models of neurological disorders such as Parkinson's and Huntington's diseases. In the current study, we examined the capability of intracerebral human MSCs transplantation (medial pre-frontal cortex) to prevent the social impairment displayed by mice after withdrawal from daily phencyclidine (PCP) administration (10 mg kg−1 daily for 14 days). Our results show that MSCs transplantation significantly prevented the PCP-induced social deficit, as assessed by the social preference test. In contrast, the PCP-induced social impairment was not modified by daily clozapine treatment. Tissue analysis revealed that the human MSCs survived in the mouse brain throughout the course of the experiment (23 days). Significantly increased cortical brain-derived neurotrophic factor levels were observed in the MSCs-treated group as compared with sham-operated controls. Furthermore, western blot analysis revealed that the ratio of phosphorylated Akt to Akt was significantly elevated in the MSCs-treated mice compared with the sham controls. Our results demonstrate that intracerebral transplantation of MSCs is beneficial in attenuating the social deficits induced by sub-chronic PCP administration. We suggest a novel therapeutic approach for the treatment of schizophrenia-like negative symptoms in animal models of the disorder. PMID:22832353

Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

PubMed

Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

2013-08-01

The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices.

PubMed

Gupta, Ishan; Young, Andrew M J

2018-05-15

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release. Copyright © 2018 Elsevier B.V. All rights reserved.

Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and neuronal density in the prefrontal cortex, striatum and hippocampus in sub-chronic phencyclidine administration rat model of schizophrenia.

PubMed

Wetchateng, Thanitsara; Piyabhan, Pritsana

2015-03-01

Cognitive deficit is a significant problem, which finally occurs in all schizophrenic patients. It can not be attenuated by any antipsychotic drugs. It is well known that changes of neuronal density are correlated with learning and memory deficits. Bacopa monnieri (Brahmi), popularly known as a cognitive enhancer; might be a novel therapeutic agentfor cognitive deficit in schizophrenia by changing cerebral neuronal density. The objective of this study was to determine the effects of Brahmi on attenuation at cognitive deficit and on the neuronal density in the prefrontal cortex, striatum and cornu ammonis subfield 1 (CA1) and 2/3 (CA2/3) of hippocampus in sub-chronic phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: PCP + Brahmi. Rats were testedfor cognitive ability by using the novel object recognition test. Neuronal density from a serial Nissl stain sections ofthe prefrontal cortex, striatum and hippocampus ofrat model ofschizophrenia were measured by using Image ProPlus software and manual counting. Sub-chronic administration of PCP results in cognitive deficits in novel object recognition task. This occurred alongside significantly increased neuronal density in CA1. The cognitive deficit was recovery to normal in PCP + Brahmi group and it occurred alongside significantly decreased neuronal density in CA1. On the other hand, significantly increased neuronal density was observed in CA2/3 of PCP + Brahmi group compared with PCP alone. Brahmi is a potential cognitive enhancer against schizophrenia. It reduces neuronal density, most likely glutamatergic neuron, which results in neuronal toxicity and cognitive deficit. Therefore, Brahmi has cognitive enhancement effect by reducing glutamatergic neuron in CAI. Moreover, it also has neurogenesis effect in CA2/3, which is needed to be investigated in the further study.

Bacopa monnieri (Brahmi) improved novel object recognition task and increased cerebral vesicular glutamate transporter type 3 in sub-chronic phencyclidine rat model of schizophrenia.

PubMed

Piyabhan, Pritsana; Wannasiri, Supaporn; Naowaboot, Jarinyaporn

2016-12-01

Reduced vesicular glutamate transporter 1 (VGLUT1) and 2 (VGLUT2) indicate glutamatergic hypofunction leading to cognitive impairment in schizophrenia. However, VGLUT3 involvement in cognitive dysfunction has not been reported in schizophrenia. Brahmi (Bacopa monnieri) might be a new treatment and prevention for cognitive deficits in schizophrenia by acting on cerebral VGLUT3 density. We aimed to study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition and cerebral VGLUT3 immunodensity in sub-chronic (2 mg/kg, Bid, ip) phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups for cognitive enhancement effect study: Group 1, Control; Group 2, PCP administration; Group 3, PCP+Brahmi. A neuroprotective-effect study was also carried out. Rats were again assigned to three groups: Group 1, Control; Group 2, PCP administration; Group 3, Brahmi+PCP. Discrimination ratio (DR) representing cognitive ability was obtained from a novel object recognition task. VGLUT3 immunodensity was measured in the prefrontal cortex, striatum and cornu ammonis fields 1-3 (CA1-3) using immunohistochemistry. We found reduced DR in the PCP group, which occurred alongside VGLUT3 reduction in all brain areas. PCP+Brahmi showed higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex and striatum. Brahmi+PCP group showed a higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex, striatum and CA1-3. We concluded that reduced cerebral VGLUT3 was involved in cognitive deficit in PCP-administrated rats. Receiving Brahmi after PCP restored cognitive deficit by increasing VGLUT3 in the prefrontal cortex and striatum. Receiving Brahmi before PCP prevented cognitive impairment by elevating VGLUT3 in prefrontal cortex, striatum and CA1-3. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia. © 2016 John Wiley & Sons Australia, Ltd.

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood.

PubMed

Shirai, Yumi; Fujita, Yuko; Hashimoto, Ryota; Ohi, Kazutaka; Yamamori, Hidenaga; Yasuda, Yuka; Ishima, Tamaki; Suganuma, Hiroyuki; Ushida, Yusuke; Takeda, Masatoshi; Hashimoto, Kenji

2015-01-01

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

Subchronic treatment with phencyclidine in adolescence leads to impaired exploratory behavior in adult rats without altering social interaction or N-methyl-D-aspartate receptor binding levels.

PubMed

Metaxas, A; Willems, R; Kooijman, E J M; Renjaän, V A; Klein, P J; Windhorst, A D; Donck, L Ver; Leysen, J E; Berckel, B N M van

2014-11-01

Although both the onset of schizophrenia and human phencyclidine (PCP) abuse typically present within the interval from adolescence to early adulthood, the majority of preclinical research employing the PCP model of schizophrenia has been conducted on neonatal or adult animals. The present study was designed to evaluate the behavioral and neurochemical sequelae of subchronic exposure to PCP in adolescence. Male 35-42-day-old Sprague Dawley rats were subcutaneously administered either saline (10 ml · kg(-1) ) or PCP hydrochloride (10 mg · kg(-1) ) once daily for a period of 14 days (n = 6/group). The animals were allowed to withdraw from treatment for 2 weeks, and their social and exploratory behaviors were subsequently assessed in adulthood by using the social interaction test. To examine the effects of adolescent PCP administration on the regulation of N-methyl-D-aspartate receptors (NMDARs), quantitative autoradiography was performed on brain sections of adult, control and PCP-withdrawn rats by using 20 nM (3) H-MK-801. Prior subchronic exposure to PCP in adolescence had no enduring effects on the reciprocal contact and noncontact social behavior of adult rats. Spontaneous rearing in response to the novel testing arena and time spent investigating its walls and floor were reduced in PCP-withdrawn animals compared with control. The long-term behavioral effects of PCP occurred in the absence of persistent deficits in spontaneous locomotion or self-grooming activity and were not mediated by altered NMDAR density. Our results document differential effects of adolescent PCP administration on the social and exploratory behaviors of adult rats, suggesting that distinct neurobiological mechanisms are involved in mediating these behaviors. Copyright © 2014 Wiley Periodicals, Inc.

Neuroprotective effects of Bacopa monnieri (Brahmi) on novel object recognition and NMDAR1 immunodensity in the prefrontal cortex, striatum and hippocampus of sub-chronic phencyclidine rat model of schizophrenia.

PubMed

Piyabhan, Pritsana; Wetchateng, Thanitsara

2014-08-01

Cognitive impairment is a major problem, which eventually develops in schizophrenia. It contributes to the patients 'functional disability and cannot be attenuated by antipsychotic drugs. Bacopa monnieri (Brahmi), a neuroprotective herbal medicine in the elderly, might be a novel neuroprotective agent for prevention of cognitive deficit in schizophrenia. To study neuroprotective effects ofBrahmi on novel object recognition task and cerebral glutamate/N-methyl-D- aspartate receptor subtype 1 (NMDAR1) immunodensity in sub-chronic phencyclidine (PCP) rat model ofschizophrenia. Rats were assigned to three groups; Group-A: Control, Group-B: PCP administration and Group- C: Brahmi + PCP. Discrimination ratio (DR) representing cognitive ability was obtainedfrom novel object recognition task. NMDAR1 immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields I (CA 1) and 2/3 (CA2/3) and dentate gyrus (DG) using immunohistochemistry. DR was significantly reduced in PCP group compared with control. This occurred alongside NMDAR1 up-regulation in CA2/3 and DG but not in prefrontal cortex, striatum or CA1. Brahmi + PCP group showed an increased DR score up to normal which occurred alongside a significantly decreased NMDARI immunodensity in CA2/3 and DG compared with PCP group. Cognitive deficit observed in rats receiving PCP was mediated by NMDAR1 up-regulation in CA2/3 and DG Interestingly, receiving Brahmi before PCP administration can restore this cognitive deficit by decreasingNMDAR1 in these brain areas. Therefore, Brahmi could be a novel neuroprotective agentfor the prevention ofcognitive deficit in schizophrenia.

Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

PubMed

Rodríguez, Guadalupe; Neugebauer, Nichole M; Yao, Katherine Lan; Meltzer, Herbert Y; Csernansky, John G; Dong, Hongxin

2017-08-01

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Δ9-THC, while mice that received Δ9-THC and PCP+Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood

PubMed Central

Shirai, Yumi; Fujita, Yuko; Hashimoto, Ryota; Ohi, Kazutaka; Yamamori, Hidenaga; Yasuda, Yuka; Ishima, Tamaki; Suganuma, Hiroyuki; Ushida, Yusuke; Takeda, Masatoshi; Hashimoto, Kenji

2015-01-01

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood. PMID:26107664

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

PubMed Central

Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

2013-01-01

The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

Bacopa monnieri (Brahmi) Enhanced Cognitive Function and Prevented Cognitive Impairment by Increasing VGLUT2 Immunodensity in Prefrontal Cortex of Sub-Chronic Phencyclidine Rat Model of Schizophrenia.

PubMed

Piyabhan, Pritsana; Wetchateng, Thanitsara

2015-04-01

Glutamatergic hypofunction is affected in schizophrenia. The decrement ofpresynaptic glutamatergic marker remarkably vesicular glutamate transporter type 1 (VGLUT1) indicates the deficit ofglutamatergic and cognitive function in schizophrenic brain. However there have been afew studies in VGLUT2. Brahmi, a traditional herbal medicine, might be a new frontier of cognitive deficit treatment and prevention in schizophrenia by changing cerebral VGLUT2 density. To study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition task and cerebral VGLUT2 immunodensity in sub-chronic phencyclidine (PCP) rat model of schizophrenia. Cognitive enhancement effect study; rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: PCP + Brahmi. Neuroprotective effect study; rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: Brahmi + PCP Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition task. VGLUT2 immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields 1 (CA1) and 2/3 (CA2/3) of hippocampus using immunohistochemistry. DR was significantly reduced in PCP group compared with control. This occurred alongside VGLUT2 reduction in prefrontal cortex, but not in striatum, CA1 or CA2/3. Both PCP + Brahmi and Brahmi + PCP groups showed an increased DR score up to normal, which occurred alongside a significantly increased VGLUT2 immunodensity in the prefrontal cortex, compared with PCP group. The decrement of VGLUT2 density in prefrontal cortex resulted in cognitive deficit in rats receiving PCP. Interestingly, receiving Brahmi after PCP administration can restore this cognitive deficit by increasing VGLUT2 density in prefrontal cortex. This investigation is defined as Brahmi's cognitive enhancement effect. Additionally, receiving Brahmi before PCP administration can also prevent cognitive impairment by elevating VGLUT2 density in prefrontal cortex. This observation indicates neuroprotective effect of Brahmi. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia.

Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats.

PubMed

Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe; Dalby, Nils Ole

2014-09-01

A compromised γ-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-D-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmission in adulthood. The present study examines prefrontal GABAergic transmission in adult rats administered with the NMDA receptor channel blocker, phencyclidine (PCP), for 3 days during the second postnatal week. Whole-cell patch-clamp recordings from pyramidal cells in PCP-treated rats showed a 22% reduction in the frequency of miniature inhibitory postsynaptic currents in layer II/III, but not in layer V pyramidal neurons of the prefrontal cortex. Furthermore, early postnatal PCP treatment caused insensitivity toward effects of the GABA transporter 1 (GAT-1) inhibitor, 1,2,5,6-tetrahydro-1-[2-[[(diphenyl-methylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid, and also diminished currents passed by δ-subunit-containing GABAA receptors in layer II/III pyramidal neurons. The observed impairments in GABAergic function are compatible with the alteration of GABAergic markers as well as cognitive dysfunction observed in early postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Anxiety does not contribute to social withdrawal in the subchronic phencyclidine rat model of schizophrenia.

PubMed

Seillier, Alexandre; Giuffrida, Andrea

2017-10-01

Social withdrawal should not be considered a direct measure of the negative symptoms of schizophrenia as it may result not only from asociality (primary negative symptom) but also from other altered processes such as anxiety. To understand the contribution of these two factors to social deficit, we investigated whether the social withdrawal observed in the subchronic phencyclidine (PCP) rat model of schizophrenia could be attributed to increased anxiety. Compared to saline controls, PCP-treated rats (5 mg/kg, twice daily for 7 days, followed by a washout period) spent significantly less time in social interaction, but did not show anxiety-like behaviors in different relevant behavioral paradigms. In addition, their social deficit was not affected by a behavioral procedure known to reduce anxiety-like behavior (repeated exposure to the same partner) nor by systemic administration of the classical anxiolytic diazepam. In contrast, PCP-induced social withdrawal was reversed by the cannabinoid agonist CP55,940, a drug with known anxiogenic properties. Furthermore, when using the social approach task, PCP-treated animals performed similarly to control animals treated with diazepam, but not to those treated with the anxiogenic compound pentylenetetrazole. Taken together, our results indicate that PCP-induced social withdrawal cannot be attributed to increased anxiety. These data are discussed in the context of primary versus secondary negative symptoms and the deficit syndrome of schizophrenia.

Effects of phencyclidine, secobarbital and diazepam on eye tracking in rhesus monkeys.

PubMed

Ando, K; Johanson, C E; Levy, D L; Yasillo, N J; Holzman, P S; Schuster, C R

1983-01-01

Rhesus monkeys were trained to track a moving disk using a procedure in which responses on a lever were reinforced with water delivery only when the disk, oscillating in a horizontal plane on a screen at a frequency of 0.4 Hz in a visual angle of 20 degrees, dimmed for a brief period. Pursuit eye movements were recorded by electrooculography (EOG). IM phencyclidine, secobarbital, and diazepam injections decreased the number of reinforced lever presses in a dose-related manner. Both secobarbital and diazepam produced episodic jerky-pursuit eye movements, while phencyclidine had no consistent effects on eye movements. Lever pressing was disrupted at doses which had little effect on the quality of smooth-pursuit eye movements in some monkeys. This separation was particularly pronounced with diazepam. The similarities of the drug effects on smooth-pursuit eye movements between the present study and human studies indicate that the present method using rhesus monkeys may be useful for predicting drug effects on eye tracking and oculomotor function in humans.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

PubMed

Yavas, Ersin; Young, Andrew M J

2017-02-15

The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

Phencyclidine Discoordinates Hippocampal Network Activity But Not Place Fields

PubMed Central

Kao, Hsin-Yi; Kenney, Jana; Kelemen, Eduard

2017-01-01

We used the psychotomimetic phencyclidine (PCP) to investigate the relationships among cognitive behavior, coordinated neural network function, and information processing within the hippocampus place cell system. We report in rats that PCP (5 mg/kg, i.p.) impairs a well learned, hippocampus-dependent place avoidance behavior in rats that requires cognitive control even when PCP is injected directly into dorsal hippocampus. PCP increases 60–100 Hz medium-freguency gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta-modulated medium-frequency and slow gamma oscillations in CA1 LFPs such that medium-frequency gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP, but the drug discoordinates the subsecond temporal organization of discharge among place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the subsecond timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation–inhibition discoordination as the root of PCP-induced cognitive impairment. SIGNIFICANCE STATEMENT Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the LFP and the discharge of a subset of pyramidal neurons called “place cells” is spatially organized such that discharge is restricted to locations called a cell's “place field.” Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition. PMID:29118102

A novel photoaffinity ligand for the phencyclidine site of the N-methyl-D-aspartate receptor labels a Mr 120,000 polypeptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sonders, M.S.; Barmettler, P.; Lee, J.A.

1990-04-25

A radiolabeled photoaffinity ligand has been developed for the N-methyl-D-aspartate (NMDA)-preferring excitatory amino acid receptor complex. (3H)3-Azido-(5S, 10R)(+)-5-methyl-10,11-dihydro-5H- dibenzo(a,d)cyclohepten-5,10-imine (3H)3-azido-MK-801 demonstrated nearly identical affinity, density of binding sites, selectivity, pH sensitivity, and pharmacological profile in reversible binding assays with guinea pig brain homogenates to those displayed by its parent compound, MK-801. When employed in a photo-labeling protocol designed to optimize specific incorporation, (3H)3-azido-MK-801 labeled a single protein band which migrated in sodium dodecyl sulfate-polyacrylamide gels with Mr = 120,000. Incorporation of tritium into this band was completely inhibited when homogenates and (3H)3-azido-MK-801 were coincubated with 10 microM phencyclidine. These datamore » suggest that the phencyclidine site of the NMDA receptor complex is at least in part comprised of a Mr = 120,000 polypeptide.« less

Phencyclidine retards autoshaping at a dose which does not suppress the required response.

PubMed

Coveney, J R; Sparber, S B

1982-06-01

Four groups of five food-deprived hooded Long-Evans rats were injected subcutaneously with saline (vehicle) or 2, 4 or 8 mg phencyclidine (PCP) hydrochloride/kg fifteen minutes before being placed for the first time into operant chambers modified to detect exploratory behaviors. Rearing was found to be more sensitive to disruption by phencyclidine than was unconditioned level touching (a measure of floor-level exploratory activities). In an autoshaping session immediately following, the group of animals given the low dose of PCP made as many lever-touch responses as the group given saline, but consumed fewer of the food pellets delivered. In addition, none of the animals in the low-dose group showed within-session shortening of the latency to respond which was observed in four of five control animals. The two other groups given higher doses of PCP demonstrated dose-related decrements in responding as well as a reduction in food pellet consumption during the first session of autoshaping. Over the next two daily autoshaping sessions, performance improved in those groups initially suppressed. Performance converged in all group by the third autoshaping session.

Atypical Antischizophrenic Drugs Prevent Changes in Cortical N-Methyl-D-Aspartate Receptors and Behavior Following Sub-chronic Phencyclidine Administration in Developing Rat Pups

PubMed Central

Anastasio, Noelle C.; Johnson, Kenneth M.

2008-01-01

We sought to determine the relationship between phencyclidine (PCP)-induced alterations in behavior and NMDAR expression in the cortex by examining the effect of antischizophrenic drug treatment on both. Sprague-Dawley rat pups were pretreated with risperidone or olanzapine prior to treatment with PCP on postnatal day 7 (PN7) or sub-chronically on PN7, 9, and 11. Pre-pulse inhibition (PPI) of acoustic startle was measured on PN24–26 and following a challenge dose of 4 mg/kg PCP, locomotor activity was measured on PN28–35. PCP treatment on PN7 did not cause a deficit in PPI, but did cause locomotor sensitization. This was prevented by both antipsychotics. PCP treatment on PN7 caused an up-regulation of NR1 and NR2B, which was not affected by either antischizophrenic drug. PCP treatment on PN7, 9, and 11 caused a deficit in PPI and a sensitized locomotor response to PCP challenge as well as an up-regulation of NR1 and NR2A, all of which were prevented by both atypical antischizophrenic drugs. These data support the hypothesis that subchronic, but not single injection PCP treatment in developing rats results in behavioral alterations that are sensitive to antipsychotic drugs and these behavioral changes observed could be related to up-regulation of cortical NR1/NR2A receptors. PMID:18544461

A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice

PubMed Central

Errico, F; D'Argenio, V; Sforazzini, F; Iasevoli, F; Squillace, M; Guerri, G; Napolitano, F; Angrisano, T; Di Maio, A; Keller, S; Vitucci, D; Galbusera, A; Chiariotti, L; Bertolino, A; de Bartolomeis, A; Salvatore, F; Gozzi, A; Usiello, A

2015-01-01

Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo−/−), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo−/− mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo−/− animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico–hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia. PMID:25689573

Phencyclidine and Chemical “Stroking”

PubMed Central

Alexander, Ranya L.

1980-01-01

The current wave of drug abuse is but the latest manifestation of the real human need for “stroking.” Drugs which affect the pleasure center of the brain are prime objects of abuse. Phencyclidine (“PCP” or “angel dust”) is a cyclohexylamine which has properties of the amphetamine-stimulants, the narcotic-depressants and the hallucinogens. Previously unrecognized population groups include children less than six years of age and pregnant women and their intoxicated offspring. Successful treatment of present and future patients must be multidisciplinary and will ultimately depend upon a clear understanding of the pharmacology, social psychology, politics, and economics of drugs of abuse. PMID:7191444

Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity.

PubMed

Sonsalla, P K; Nicklas, W J; Heikkila, R E

1989-01-20

The systemic administration of either methamphetamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to experimental animals produces degenerative changes in nigrostriatal dopaminergic neurons or their axon terminals. This study was conducted to determine if excitatory amino acids, which appear to be involved in various neurodegenerative disorders, might also contribute to the dopaminergic neurotoxicity produced in mice by either methamphetamine or MPTP. MK-801, phencyclidine, and ketamine, noncompetitive antagonists of one subtype of excitatory amino acid receptor, the N-methyl-D-aspartate receptor, provided substantial protection against neurotoxicity produced by methamphetamine but not that produced by MPTP. These findings indicate that excitatory amino acids play an important role in the nigrostriatal dopaminergic damage induced by methamphetamine.

Effects of withdrawal from repeated phencyclidine administration on behavioural function and brain arginine metabolism in rats.

PubMed

Knox, Logan T; Jing, Yu; Bawazier-Edgecombe, Jamal; Collie, Nicola D; Zhang, Hu; Liu, Ping

2017-02-01

Phencyclidine (PCP) induces behavioural changes in humans and laboratory animals that resemble positive and negative symptoms, and cognitive impairments in schizophrenia. It has been shown repeated treatment of PCP leading to persistent symptoms even after the drug discontinuation, and there is a growing body of evidence implicating altered arginine metabolism in the pathogenesis of schizophrenia. The present study investigated the effects of withdrawal from repeated daily injection of PCP (2mg/kg) for 12 consecutive days on animals'behavioural performance and arginine metabolism in the hippocampus and prefrontal cortex in male young adult rats. Repeated PCP treatment reduced spontaneous alternations in the Y-maze and exploratory and locomotor activities in the open field under the condition of a washout period of 24h, but not 4days. Interestingly, the PCP treated rats also displayed spatial working memory deficits when tested 8-10days after withdrawal from PCP and showed altered levels of arginase activities and eight out of ten l-arginine metabolites in neurochemical- and region-specific manner. Cluster analyses showed altered relationships among l-arginine and its three main metabolites as a function of withdrawal from repeated PCP treatment in a duration-specific manner. Multiple regression analysis revealed significant neurochemical-behavioural correlations. Collectively, the results suggest both the residual and long-term effects of withdrawal from repeated PCP treatment on behavioural function and brain arginine metabolism. These findings demonstrate, for the first time, the influence of the withdrawal duration on animals' behaviour and brain arginine metabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

Drug discrimination under two concurrent fixed-interval fixed-interval schedules.

PubMed

McMillan, D E; Li, M

2000-07-01

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-interval (FI) 100-s FI 200-s schedule of food presentation, and later tinder a concurrent FI 40-s FI 80-s schedule, in which the FI component with the shorter time requirement reinforced responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized under the concurrent FI 100-s FI 200-s schedule, pigeons earned an average of 66% (after pentobarbital) to 68% (after saline) of their reinforcers for responding under the FI 100-s component of the concurrent schedule. These birds made an average of 70% of their responses on both the pentobarbital-biased key after the training dose of pentobarbital and the saline-biased key after saline. After responding stabilized under the concurrent FI 40-s FI 80-s schedule, pigeons earned an average of 67% of their reinforcers for responding under the FI 40 component after both saline and the training dose of pentobarbital. These birds made an average of 75% of their responses on the pentobarbital-biased key after the training dose of pentobarbital, but only 55% of their responses on the saline-biased key after saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, ethanol, phencyclidine, or methamphetamine, the dose-response curves were similar under these two concurrent schedules. Pentobarbital, chlordiazepoxide, and ethanol produced dose-dependent increases in responding on the pentobarbital-biased key as the doses increased. For some birds, at the highest doses of these drugs, the dose-response curve turned over. Increasing doses of phencyclidine produced increased responding on the pentobarbital-biased key in some, but not all, birds. After methamphetamine, responding was largely confined to the saline-biased key. These data show that pigeons can perform drug discriminations under concurrent schedules in which the reinforcement frequency under the schedule components differs only by a factor of two, and that when other drugs are substituted for the training drugs they produce dose-response curves similar to the curves produced by these drugs under other concurrent interval schedules.

Phencyclidine and Scopolamine for Modeling Amnesia in Rodents: Direct Comparison with the Use of Barnes Maze Test and Contextual Fear Conditioning Test in Mice.

PubMed

Malikowska-Racia, Natalia; Podkowa, Adrian; Sałat, Kinga

2018-04-21

Nowadays cognitive impairments are a growing unresolved medical issue which may accompany many diseases and therapies, furthermore, numerous researchers investigate various neurobiological aspects of human memory to find possible ways to improve it. Until any other method is discovered, in vivo studies remain the only available tool for memory evaluation. At first, researchers need to choose a model of amnesia which may strongly influence observed results. Thereby a deeper insight into a model itself may increase the quality and reliability of results. The most common method to impair memory in rodents is the pretreatment with drugs that disrupt learning and memory. Taking this into consideration, we compared the activity of agents commonly used for this purpose. We investigated effects of phencyclidine (PCP), a non-competitive NMDA receptor antagonist, and scopolamine (SCOP), an antagonist of muscarinic receptors, on short-term spatial memory and classical fear conditioning in mice. PCP (3 mg/kg) and SCOP (1 mg/kg) were administrated intraperitoneally 30 min before behavioral paradigms. To assess the influence of PCP and SCOP on short-term spatial memory, the Barnes maze test in C57BL/J6 mice was used. Effects on classical conditioning were evaluated using contextual fear conditioning test. Additionally, spontaneous locomotor activity of mice was measured. These two tests were performed in CD-1 mice. Our study reports that both tested agents disturbed short-term spatial memory in the Barnes maze test, however, SCOP revealed a higher activity. Surprisingly, learning in contextual fear conditioning test was impaired only by SCOP. Graphical Abstract ᅟ.

Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain.

PubMed

Troyano-Rodriguez, Eva; Lladó-Pelfort, Laia; Santana, Noemi; Teruel-Martí, Vicent; Celada, Pau; Artigas, Francesc

2014-12-15

The neurobiological basis of action of noncompetitive N-methyl-D-aspartate acid receptor (NMDA-R) antagonists is poorly understood. Electrophysiological studies indicate that phencyclidine (PCP) markedly disrupts neuronal activity with an overall excitatory effect and reduces the power of low-frequency oscillations (LFO; <4 Hz) in thalamocortical networks. Because the reticular nucleus of the thalamus (RtN) provides tonic feed-forward inhibition to the rest of the thalamic nuclei, we examined the effect of PCP on RtN activity, under the working hypothesis that NMDA-R blockade in RtN would disinhibit thalamocortical networks. Drug effects (PCP followed by clozapine) on the activity of RtN (single unit and local field potential recordings) and prefrontal cortex (PFC; electrocorticogram) in anesthetized rats were assessed. PCP (.25-.5 mg/kg, intravenous) reduced the discharge rate of 19 of 21 RtN neurons to 37% of baseline (p < .000001) and the power of LFO in RtN and PFC to ~20% of baseline (p < .001). PCP also reduced the coherence between PFC and RtN in the LFO range. A low clozapine dose (1 mg/kg intravenous) significantly countered the effect of PCP on LFO in PFC but not in RtN and further reduced the discharge rate of RtN neurons. However, clozapine administration partly antagonized the fall in coherence and phase-locking values produced by PCP. PCP activates thalamocortical circuits in a bottom-up manner by reducing the activity of RtN neurons, which tonically inhibit thalamic relay neurons. However, clozapine reversal of PCP effects is not driven by restoring RtN activity and may involve a cortical action. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

PubMed Central

Baker, David. A.; Madayag, Aric; Kristiansen, Lars V.; Meador-Woodruff, James H.; Haroutunian, Vahram; Raju, Ilangovan

2014-01-01

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex; an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial T-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Lastly, protein levels from post mortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP. PMID:17728701

SELECTIVE POTENTIATION OF THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 2 BLOCKS PHENCYCLIDINE-INDUCED HYPERLOCOMOTION AND BRAIN ACTIVATION

PubMed Central

HACKLER, E. A.; BYUN, N. E.; JONES, C. K.; WILLIAMS, J. M.; BAHEZA, R.; SENGUPTA, S.; GRIER, M. D.; AVISON, M.; CONN, P. J.; GORE, J. C.

2013-01-01

Previous preclinical and clinical studies have demonstrated the efficacy of group II metabotropic glutamate receptor (mGluR) agonists as potential antipsychotics. Recent studies utilizing mGluR2-, mGluR3-, and double knockout mice support that the antipsychotic effects of those compounds are mediated by mGluR2. Indeed, biphenyl indanone-A (BINA), an allosteric potentiator of mGluR2, is effective in experimental models of psychosis, blocking phencyclidine (PCP)-induced hyperlocomotion and prepulse inhibition deficits in mice. In this study, we administered the NMDA receptor antagonist PCP (5.6 mg/kg i.p.) to rats, an established animal model predictive of schizophrenia. Here, we show that BINA (32 mg/kg i.p.) attenuated PCP-induced locomotor activity in rats. Using behaviorally relevant doses of BINA and PCP, we performed pharmacological magnetic resonance imaging (phMRI) to assess the specific brain regions that underlie the psychotomimetic effects of PCP, and examined how BINA modulated the PCP-induced functional changes in vivo. In anesthetized rats, acute administration of PCP produced robust, sustained blood oxygenation level-dependent (BOLD) activation in specific cortical, limbic, thalamic, and striatal regions. Pretreatment with BINA suppressed the amplitude of the BOLD response to PCP in the prefrontal cortex, caudaute–putamen, nucleus accumbens, and mediodorsal thalamus. Our results show key brain structures underlying PCP-induced behaviors in a preclinical model of schizophrenia, and, importantly, its reversal by potentiation of mGluR2 by BINA, revealing specific brain regions functionally involved in its pharmacological action. Finally, our findings bolster the growing body of evidence that mGluR2 is a viable target for the treatment of schizophrenia. PMID:20350588

Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine

PubMed Central

Bullock, W. Michael; Bolognani, Federico; Botta, Paolo; Valenzuela, C. Fernando; Perrone-Bizzozero, Nora I.

2009-01-01

One of the most consistent findings in schizophrenia is the decreased expression of the GABA synthesizing enzymes GAD67 and GAD65 in specific interneuron populations. This dysfunction is observed in distributed brain regions including the prefrontal cortex, hippocampus, and cerebellum. In an effort to understand the mechanisms for this GABA deficit, we investigated the effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms in both humans and animal models, in a chronic, low-dose exposure paradigm. Adult rats were given PCP at a dose of 2.58 mg/kg/day i.p. for a month, after which levels of various GABAergic cell mRNAs and other neuromodulators were examined in the cerebellum by RT-qPCR. Administration of PCP decreased the expression of GAD67, GAD65, and the presynaptic GABA transporter GAT-1, and increased GABAA receptor subunits similar to those seen in patients with schizophrenia. Additionally, we found that the mRNA levels of two Golgi cell selective NMDAR subunits, NR2B and NR2D, were decreased in PCP treated rats. Furthermore, we localized the deficits in GAD67 expression solely to these interneurons. Slice electrophysiological studies showed that spontaneous firing of Golgi cells was reduced by acute exposure to low dose PCP, suggesting that these neurons are particularly vulnerable to NMDA receptor antagonism. In conclusion, our results demonstrate that chronic exposure to low levels of PCP in rats mimics the GABAergic alterations reported in the cerebellum of patients with schizophrenia (Bullock et al., Am J Psychiatry 165: 1594-1603, 2008), further supporting the validity of this animal model. PMID:19651169

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics.

PubMed

Seeman, P; Ko, F; Tallerico, T

2005-09-01

Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2High, their dissociation constants (Ki) were obtained on [3H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2High with a Ki of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a Ki of 313 nM, as labeled by [3H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites. Dizocilpine had a Ki of 0.3 nM at D2High, but a Kd of 1.8 nM at the NMDA receptor. LSD had a Ki of 2 nM at D2High. Because the psychotomimetics had higher potency at D2High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis.

Interaction of ( sup 3 H)MK-801 with multiple states of the N-methyl-D-aspartate receptor complex of rat brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Javitt, D.C.; Zukin, S.R.

1989-01-01

N-Methyl-D-aspartate (N-Me-D-Asp) and phencyclidine receptors interactively mediate central nervous system processes including psychotomimetic effects of drugs as well as neurodegenerative, cognitive, and developmental events. To elucidate the mechanism of this interaction, effects of N-Me-D-Asp agonists and antagonists and of glycine-like agents upon binding of the radiolabeled phencyclidine receptor ligand ({sup 3}H)MK-801 were determined in rat brain. Scatchard analysis revealed two discrete components of ({sup 3}H)MK-801 binding after 4 hr of incubation. Incubation in the presence of L-glutamate led to an increase in apparent densities but not in affinities of both components of ({sup 3}H)MK-801 binding as well as conversion ofmore » sites from apparent low to high affinity. Incubation in the presence of combined D-serine and L-glutamate led to an increase in the apparent density of high-affinity ({sup 3}H)MK-801 binding compared with incubation in the presence of either L-glutamate or D-serine alone. These data support a model in which phencyclidine receptor ligands bind differentially to closed as well as open conformations of the N-Me-D-Asp receptor complex and in which glycine-like agents permit or facilitate agonist-induced conversion of N-Me-D-Asp receptors from closed to open conformations.« less

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Substance abuse vaccines.

PubMed

Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Gardner, Tracie; Kosten, Thomas R

2008-10-01

Conventional substance-abuse treatments have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and phencyclidine. New approaches, including vaccination to block the effects of these drugs on the brain, are in advanced stages of development. Although several potential mechanisms for the effects of antidrug vaccines have been suggested, the most straightforward and intuitive mechanism involves binding of the drug by antibodies in the bloodstream, thereby blocking entry and/or reducing the rate of entry of the drug into the central nervous system. The benefits of such antibodies on drug pharmacodynamics will be influenced by both the quantitative and the qualitative properties of the antibodies. The sum of these effects will determine the success of the clinical applications of antidrug vaccines in addiction medicine. This review will discuss these issues and present the current status of vaccine development for nicotine, cocaine, methamphetamine, phencyclidine, and morphine.

Stability of drugs of abuse in urine samples stored at -20 degrees C.

PubMed

Dugan, S; Bogema, S; Schwartz, R W; Lappas, N T

1994-01-01

Isolated studies of the stability of individual drugs of abuse have been reported. However, few have evaluated stability in frozen urine samples stored for 12 months. We have determined the stability of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (9-COOH-THC), amphetamine, methamphetamine, morphine, codeine, cocaine, benzoylecgonine, and phencyclidine in 236 physiological urine samples. Following the initial quantitative analysis, the samples were stored at -20 degrees C for 12 months and then reanalyzed. All drug concentrations were determined by gas chromatographic-mass spectrometric methods with cutoff concentrations of 5 ng/mL for 9-COOH-THC and phencyclidine and 100 ng/mL for each of the other drugs. The average change in the concentrations of these drugs following this long-term storage was not extensive except for an average change of -37% in cocaine concentrations.

THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

PubMed

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2016-02-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the sub-chronic PCP model of schizophrenia

PubMed Central

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2017-01-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the CSF levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared to THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. PMID:26510449

Phencyclidine overdose

MedlinePlus

... time between taking the drug and receiving treatment Recovery from the psychotic state may take several weeks. The person should be in a quiet, darkened room. Long-term effects may include kidney failure and seizures. Repeated PCP use may cause long- ...

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2010-12-03

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Micro-solid phase extraction coupled with high-performance liquid chromatography-tandem mass spectrometry for the determination of stimulants, hallucinogens, ketamine and phencyclidine in oral fluids.

PubMed

Sergi, Manuel; Compagnone, Dario; Curini, Roberta; D'Ascenzo, Giuseppe; Del Carlo, Michele; Napoletano, Sabino; Risoluti, Roberta

2010-08-24

A confirmatory method for the determination of illicit drugs based on micro-solid phase extraction with modified tips, made of a functionalized fiberglass with apolar chains of octadecylsilane into monolithic structure, has been developed in this study. Drugs belonging to different chemical classes, such as amphetamine, methamphetamine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethylamphetamine, cocaine, benzoylecgonine, ketamine, mescaline, phencyclidine and psilocybine were analyzed. The quantitation was performed by liquid chromatography-tandem mass spectrometry and the analytes were detected in positive ionization by means of an electrospray source. The limits of quantification ranged between 0.3 ng mL(-1) for cocaine and 4.9 ng mL(-1) for psilocybine, with coefficients of determination (r(2)) >0.99 for all the analytes as recommended in the guidelines of Society of Forensic Toxicologists-American Association Forensic Sciences. 2010 Elsevier B.V. All rights reserved.

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.

PubMed

Andrews, Jessica L; Newell, Kelly A; Matosin, Natalie; Huang, Xu-Feng; Fernandez-Enright, Francesca

2015-12-03

Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia. Copyright © 2015 Elsevier Inc. All rights reserved.

Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review.

PubMed

Grayson, B; Barnes, S A; Markou, A; Piercy, C; Podda, G; Neill, J C

Cognitive dysfunction and negative symptoms of schizophrenia remain an unmet clinical need. Therefore, it is essential that new treatments and approaches are developed to recover the cognitive and social impairments that are seen in patients with schizophrenia. These may only be discovered through the use of carefully validated, aetiologically relevant and translational animal models. With recent renewed interest in the neurodevelopmental hypothesis of schizophrenia, postnatal administration of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) has been proposed as a model that can mimic aspects of schizophrenia pathophysiology. The purpose of the current review is to examine the validity of this model and compare it with the adult subchronic PCP model. We review the ability of postnatal PCP administration to produce behaviours (specifically cognitive deficits) and neuropathology of relevance to schizophrenia and their subsequent reversal by pharmacological treatments. We review studies investigating effects of postnatal PCP on cognitive domains in schizophrenia in rats. Morris water maze and delayed spontaneous alternation tasks have been used for working memory, attentional set-shifting for executive function, social novelty discrimination for selective attention and prepulse inhibition of acoustic startle for sensorimotor gating. In addition, we review studies on locomotor activity and neuropathology. We also include two studies using dual hit models incorporating postnatal PCP and two studies on social behaviour deficits following postnatal PCP. Overall, the evidence we provide supports the use of postnatal PCP to model cognitive and neuropathological disturbances of relevance to schizophrenia. To date, there is a lack of evidence to support a significant advantage of postnatal PCP over the adult subchronic PCP model and full advantage has not been taken of its neurodevelopmental component. When thoroughly characterised, it is likely that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs).

Postmortem diagnosis and toxicological validation of illicit substance use

PubMed Central

Lehrmann, E; Afanador, ZR; Deep-Soboslay, A; Gallegos, G; Darwin, WD; Lowe, RH; Barnes, AJ; Huestis, MA; Cadet, JL; Herman, MM; Hyde, TM; Kleinman, JE; Freed, WJ

2008-01-01

The present study examines the diagnostic challenges of identifying ante-mortem illicit substance use in human postmortem cases. Substance use, assessed by clinical case history reviews, structured next-of-kin interviews, by general toxicology of blood, urine, and/or brain, and by scalp hair testing, identified 33 cocaine, 29 cannabis, 10 phencyclidine and 9 opioid cases. Case history identified 42% cocaine, 76% cannabis, 10% phencyclidine, and 33% opioid cases. Next-of-kin interviews identified almost twice as many cocaine and cannabis cases as Medical Examiner (ME) case histories, and were crucial in establishing a detailed lifetime substance use history. Toxicology identified 91% cocaine, 68% cannabis, 80% phencyclidine, and 100% opioid cases, with hair testing increasing detection for all drug classes. A cocaine or cannabis use history was corroborated by general toxicology with 50% and 32% sensitivity, respectively, and with 82% and 64% sensitivity by hair testing. Hair testing corroborated a positive general toxicology for cocaine and cannabis with 91% and 100% sensitivity, respectively. Case history corroborated hair toxicology with 38% sensitivity for cocaine and 79% sensitivity for cannabis, suggesting that both case history and general toxicology underestimated cocaine use. Identifying ante-mortem substance use in human postmortem cases are key considerations in case diagnosis and for characterization of disorder-specific changes in neurobiology. The sensitivity and specificity of substance use assessments increased when ME case history was supplemented with structured next-of-kin interviews to establish a detailed lifetime substance use history, while comprehensive toxicology, and hair testing in particular, increased detection of recent illicit substance use. PMID:18201295

Asenapine Effects on Cognitive and Monoamine Dysfunction Elicited by Subchronic Phencyclidine Administration

PubMed Central

Elsworth, John D.; Groman, Stephanie; Jentsch, J. David; Valles, Rodrigo; Shahid, Mohammed; Wong, Erik; Marston, Hugh; Roth, Robert H.

2013-01-01

Purpose Repeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort. Methods Monkeys were trained to perform reversal learning and object retrieval procedures before twice-daily administration of PCP (0.3 mg/kg intramuscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice-daily administration of saline (control) or asenapine (50, 100, or 150 μg/kg, intramuscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite. Results On average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2–4 weeks of dosing. In week 4, the improvement with asenapine 150 μg/kg (p=0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 μg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50–150 μg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit. Conclusions In this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder. PMID:21875607

Drug and alcohol testing results 1996 annual report

DOT National Transportation Integrated Search

1997-12-01

The report is a compilation and analysis of mass transit drug and alcohol testing reported by transit systems in the United States during 1996. The report covers testing results for the following drug types: marijuana (THC), cocaine, phencyclidine (P...

Drug and Alcohol Testing Results - 1995 Annual Report

DOT National Transportation Integrated Search

1997-03-01

The Report is a compilation and analysis of mass transit drug and alcohol testing reported by transit systems in the United States during 1995. The report covers testing for alcohol and the following drug types: marijuana (THC), cocaine, phencyclidin...

Determination of five abused drugs in nitrite-adulterated urine by immunoassays and gas chromatography-mass spectrometry.

PubMed

Tsai, S C; ElSohly, M A; Dubrovsky, T; Twarowska, B; Towt, J; Salamone, S J

1998-10-01

The adulteration of urine specimens with nitrite ion hasseen shown to mask the gas chromatography-mass spectrometry (GC-MS) confirmation testing of marijuana use. This study was designed to further investigate the effect of nitrite adulteration on the detection of five commonly abused drugs by immunoassay screening and GC-MS analysis. The drugs tested are cocaine metabolite (benzoylecgonine), morphine, 11-nor-delta-tetrahydrocannabinol-9-carboxylic acid (THCCOOH), amphetamine, and phencyclidine. The immunoassays evaluated included the instrument-based Abuscreen ONLINE assays, the on-site Abuscreen ONTRAK assays, and the one-step ONTRAK TESTCUP-5 assay. Multianalyte standards containing various levels of drugs were used to test the influence of both potassium and sodium nitrite. In the ONLINE immunoassays, the presence of up to 1.0M nitrite in the multianalyte standards had no significant effect for benzoylecgonine, morphine, and phencyclidine assays. With a high concentration of nitrite, ONLINE became more sensitive for amphetamine (detected more drug than what was expected) and less sensitive for THCCOOH (detected less drug than what was expected). No effects of nitrite were observed on the results of the Abuscreen ONTRAK assays. Similarly, no effects were observed on the absolute qualitative results of the TESTCUP-5 when testing the nitrite-adulterated standards. However, the produced intensities of the signals that indicate the negative test results were slightly lowered in the THC and phencyclidine assays. The presence of 1.0M of nitrite did not show dramatic interference with the GC-MS analysis of benzoylecgonine, morphine, amphetamine, and phencyclidine. In contrast, nitrite ion significantly interfered with the detection of THCCOOH by GC-MS. The presence of 0.03M of nitrite ion resulted in significant loss in the recovery of THCCOOH and its internal standard by GC-MS. The problem of nitrite adulteration could be alleviated by sodium bisulfite treatment even when the specimens were spiked with 1.0M of nitrite ion. Although bisulfite treatment decomposed all nitrite ions in the sample to recover the remaining THCCOOH by GC-MS, the net recovery of THCCOOH depended on urinary pH and time and conditions of sample storage. The presence of nitrite concentrations that might arise from all possible natural sources, including microorganisms, pathological conditions, and medications, did not interfere with the GC-MS analysis of THCCOOH.

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice.

PubMed

Arime, Yosefu; Akiyama, Kazufumi

2017-01-01

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2-3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2-3 of the prelimbic cortex of the PFC.

Blonanserin reverses the phencyclidine (PCP)-induced impairment in novel object recognition (NOR) in rats: role of indirect 5-HT(1A) partial agonism.

PubMed

Horiguchi, M; Meltzer, H Y

2013-06-15

Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2 mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3 mg/kg) and the 5-HT1A partial agonist, tandospirone (0.2 mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6 mg/kg), a 5-HT1A antagonist, and blonanserin (1 mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6 mg/kg) blocked the ameliorating effect of risperidone (0.1 mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects. Copyright © 2013 Elsevier B.V. All rights reserved.

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice

PubMed Central

Akiyama, Kazufumi

2017-01-01

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2–3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2–3 of the prelimbic cortex of the PFC. PMID:29253020

Identification of Developmentally Regulated PCP-Responsive Non-Coding RNA, prt6, in the Rat Thalamus

PubMed Central

Umino, Asami; Nishikawa, Toru

2014-01-01

Schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, usually develop after adolescence. Moreover, adult-type behavioral disturbance following NMDA receptor antagonist application in rodents is observed after a critical period at around 3 postnatal weeks. These observations suggest that the schizophrenic symptoms caused by and psychotomimetic effects of NMDA antagonists require the maturation of certain brain neuron circuits and molecular networks, which differentially respond to NMDA receptor antagonists across adolescence and the critical period. From this viewpoint, we have identified a novel developmentally regulated phencyclidine-responsive transcript from the rat thalamus, designated as prt6, as a candidate molecule involved in the above schizophrenia-related systems using a DNA microarray technique. The transcript is a non-coding RNA that includes sequences of at least two microRNAs, miR132 and miR212, and is expressed strongly in the brain and testis, with trace or non-detectable levels in the spleen, heart, liver, kidney, lung and skeletal muscle, as revealed by Northern blot analysis. The systemic administration of PCP (7.5 mg/kg, subcutaneously (s.c.)) significantly elevated the expression of prt6 mRNA in the thalamus at postnatal days (PD) 32 and 50, but not at PD 8, 13, 20, or 24 as compared to saline-treated controls. At PD 50, another NMDA receptor antagonist, dizocilpine (0.5 mg/kg, s.c.), and a schizophrenomimetic dopamine agonist, methamphetamine (4.8 mg/kg, s.c.), mimicked a significant increase in the levels of thalamic prt6 mRNAs, while a D2 dopmamine receptor antagonist, haloperidol, partly inhibited the increasing influence of PCP on thalamic prt6 expression without its own effects. These data indicate that prt6 may be involved in the pathophysiology of the onset of drug-induced schizophrenia-like symptoms and schizophrenia through the possible dysregulation of target genes of the long non-coding RNA or microRNAs in the transcript. PMID:24886782

77 FR 67675 - Importer of Controlled Substances, Notice of Registration, SA INTL GMBH C/O., Sigma Aldrich Co...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-13

... (2315) II Glutethimide (2550) II Nabilone (7379) II Phencyclidine (7471) II Cocaine (9041) II Codeine... international treaties, conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated...

Personnel Security Research - Prescreening and Background Investigations

DTIC Science & Technology

1986-06-01

military unit, base, station, ship, or aircraft nf a controlled substance with the intent to distribute. Hallucinogens/ Psychedelics . A group of...and psychedelic amphetamine variants (STP, MDA). Although a unique drug, for purposes of this certificate phencyclidine (PCP) will be labeled in this

Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats.

PubMed

Eppolito, Amy K; Kodeih, Hanna R; Gerak, Lisa R

2014-10-01

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone. Copyright © 2014 Elsevier Inc. All rights reserved.

Identification and quantification of phencyclidine pyrolysis products formed during smoking.

PubMed

Lue, L P; Scimeca, J A; Thomas, B F; Martin, B R

1986-01-01

As a result of frequent phencyclidine (PCP) abuse, pyrolysis studies were conducted to further investigate its fate during smoking. Marijuana placebo cigarettes were impregnated with 3H-PCP X HCI and burned under conditions simulating smoking. Mainstream smoke was passed through glass wool filters as well as acidic and basic traps. Approximately 90% of the starting material could be accounted for in the first glass wool trap and cigarette holder. HPLC and GC/MS analysis of methanol extracts of these glass wool traps revealed the presence of 1-phenyl-1-cyclohexene (47% of the starting material) greater than PCP (40%) greater than piperidine (15%) greater than N-acetylpiperidine (9%). It was not possible to fully account for the remainder of the piperidine moiety. It has been reported that at high temperatures PCP is converted to numerous polynuclear aromatic compounds which include styrene, alpha-methylstyrene, naphthalene, 2-methylnaphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions.

Desensitization of the nicotinic acetylcholine receptor by diisopropylfluorophosphate.

PubMed

Eldefrawi, M E; Schweizer, G; Bakry, N M; Valdes, J J

1988-01-01

The interaction of diisopropylfluorophosphate (DFP) with the nicotinic acetylcholine (ACh) receptor of Torpedo electric organ was studied, using [3H]-phencyclidine ([3H]-PCP) as a reporter probe. Phencyclidine binds with different kinetics to resting, activated, and desensitized receptor conformations. Although DFP did not inhibit binding of [3H]-ACh or 125I-alpha-bungarotoxin (BGT) to the receptor recognition sites and potentiated in a time-dependent manner [3H]-PCP binding to the receptor's high-affinity allosteric site, it inhibited the ACh- or carbamylcholine-stimulated [3H]-PCP binding. This suggested that DFP bound to a third kind of site on the receptor and affected receptor conformation. Preincubation of the membranes with DFP increased the receptor's affinity for carbamylcholine by eightfold and raised the pseudo-first-order rate of [3H]-PCP binding to that of an agonist-desensitized receptor. Accordingly, it is suggested that DFP induces receptor desensitization by binding to a site that is distinct from the recognition or high-affinity noncompetitive sites.

Identification and quantification of phencyclidine pyrolysis products formed during smoking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lue, L.P.; Scimeca, J.A.; Thomas, B.F.

As a result of frequent phencyclidine (PCP) abuse, pyrolysis studies were conducted to further investigate its fate during smoking. Marijuana placebo cigarettes were impregnated with /sup 3/H-PCP HCl and burned under conditions simulating smoking. Mainstream smoke was passed through glass wool filters as well as acidic and basic traps. Approximately 90% of the starting material could be accounted for in the first glass wool trap and cigarette holder. HPLC and GC/MS analysis of methanol extracts of these glass wool traps revealed the presence of 1-phenyl-1-cyclohexene (47% of the starting material) > PCP (40%) > piperidine (15%) > N-acetylpiperidine (9%). Itmore » was not possible to fully account for the remainder of the piperidine moiety. It has been reported that at high temperatures PCP is converted to numerous polynuclear aromatic compounds which include styrene, ..cap alpha..-methylstyrene, naphthalene, 2-methyl-naphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions.« less

77 FR 29307 - Control of Alcohol and Drug Use: Addition of Post-Accident Toxicological Testing for Non...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-17

... post-accident testing, FRA routinely conducts tests for alcohol, marijuana, cocaine, phencyclidine (PCP..., as part of its accident investigation program, FRA has conducted post-accident alcohol and drug tests... conduct post-accident tests for any substance (e.g., carbon [[Page 29308

77 FR 10509 - Agency Information Collection Activities; Proposed Collection; Comment Request; Drug Testing for...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-22

... Activities; Proposed Collection; Comment Request; Drug Testing for Contract Employees (Renewal) AGENCY... electronic docket, go to www.regulations.gov . Title: Drug Testing for Contract Employees. ICR numbers: EPA..., amphetamines, phencyclidine (PCP), and any other controlled substances. The testing for drugs must be completed...

Is the Acute NMDA Receptor Hypofunction a Valid Model of Schizophrenia?

PubMed Central

Adell, Albert; Jiménez-Sánchez, Laura; López-Gil, Xavier; Romón, Tamara

2012-01-01

Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD67) is at variance with human studies. It is possible that changes in GAD67 are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity. PMID:21965469

A Nonpharmacologic Method for Enhancing Sleep in PTSD

DTIC Science & Technology

2015-10-01

medications include: Alcohol (during intoxication or withdrawal); cannabis (during intoxication); hallucinogens (during intoxication), phencyclidine... medications are taken solely under appropriate medical supervision, this criterion is not considered to be met. SEDATIVE/ HYPNOTIC/ANX CANNABIS ...are taken solely under appropriate medical supervision, this criterion is not considered to be met. SEDATIVE/ HYPNOTIC/ANX CANNABIS STIMULANTS

Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex.

PubMed

McClatchy, D B; Savas, J N; Martínez-Bartolomé, S; Park, S K; Maher, P; Powell, S B; Yates, J R

2016-02-01

Prepulse inhibition (PPI) is an example of sensorimotor gating and deficits in PPI have been demonstrated in schizophrenia patients. Phencyclidine (PCP) suppression of PPI in animals has been studied to elucidate the pathological elements of schizophrenia. However, the molecular mechanisms underlying PCP treatment or PPI in the brain are still poorly understood. In this study, quantitative phosphoproteomic analysis was performed on the prefrontal cortex from rats that were subjected to PPI after being systemically injected with PCP or saline. PCP downregulated phosphorylation events were significantly enriched in proteins associated with long-term potentiation (LTP). Importantly, this data set identifies functionally novel phosphorylation sites on known LTP-associated signaling molecules. In addition, mutagenesis of a significantly altered phosphorylation site on xCT (SLC7A11), the light chain of system xc-, the cystine/glutamate antiporter, suggests that PCP also regulates the activity of this protein. Finally, new insights were also derived on PPI signaling independent of PCP treatment. This is the first quantitative phosphorylation proteomic analysis providing new molecular insights into sensorimotor gating.

Field applications of ion-mobility spectrometry

NASA Astrophysics Data System (ADS)

Brown, Patricia A.

1997-02-01

Ion mobility spectrometry (IMS) is an excellent tool for detection of controlled substances under field conditions. Plasmagrams and tables showing the results of field applications will be discussed. Residues of drugs, such as cocaine and heroin, can be left anywhere including vehicles, boats, and houses. In houses, the carpets, walls, and floors are good locations for residues to adhere. Individual clothing can also be contaminated with drug residue. Vehicles that are suspected of having previously smuggled illegal substances can be vacuumed and screened. Tablets that look similar and respond the same when screened with the Marquis reagent can be differentiated by IMS. With Southern California being the 'methamphetamine capital of the world' and the resurgence of phencyclidine, IMS has proven extremely valuable in the screening of abandoned clandestine laboratory sites and vehicles in which the clandestine laboratories; chemicals and glassware were transported. IMS is very responsive to ephedrine/pseudophedrine, a precursor of methamphetamine and 1-piperidinocyclohexanecarbonitrile, an intermediate of phencyclidine. Once residues are detected, vacuum samples, and/or methanol wipes are collected and analyzed at the DEA Laboratory for confirmation of the suspected substance using GC-IRD or Mass Spectrometry.

Synthesis and characterization of a radiolabeled derivative of the phencyclidine/N-methyl-D-aspartate receptor ligand (+)MK-801 with high specific radioactivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keana, J.F.W.; Scherz, M.W.; Quarum, M.

1988-01-01

A (/sup 3/H)-labelled derivative of the drug (+)MK-801 with a high specific radioactivity was synthesized by first preparing a tribromo derivative of (+)MK-801 followed by catalytic reduction in the presence of (/sup 3/H)-gas and subsequent purification of the radioactive product by reversed-phase high performance liquid chromatography (RP-HPLC). This resulted in pure (+) (/sup 3/H)MK-801 with a specific radioactivity of 97 Ci/mmol. The (+) (/sup 3/H)MK-801 was shown to interact with high affinity and selectivity with the phencyclidine (PCP) receptor in guinea pig brain membrane suspensions. The PCP receptor is associated with a cation channel that is chemically gated by glutamatemore » and N-methyl-D-aspartate (NMDA). Drugs that interact with the PCP receptor block this channel. The (+) (/sup 3/H)MK-801 described here will be useful to investigate the biochemistry of PCP/NMDA receptors in experiments where a high specific radioactivity is essential.« less

Acetylcholine-Like Molecular Arrangement in Psychomimetic Anticholinergic Drugs

PubMed Central

Maayani, Saul; Weinstein, Harel; Cohen, Sasson; Sokolovsky, Mordechai

1973-01-01

A study of the relation between the psychotropic activity and the antagonism to acetylcholine observed for some heterocyclic amino esters and compounds of the phencyclidine series suggests some common molecular structural requirements for their properties. Criteria obtained from quantum mechanical calculations of acetylcholine-like molecules indicate that their molecular reactivity with the cholinergic receptor site follows a certain dynamic interaction pattern. This pattern suggests a certain molecular arrangement essential for the interaction, which is based on the electronic properties of the molecules and therefore remains valid for the evaluation of compounds which lack any apparent similarity to acetylcholine. This type of molecular arrangement is shown to be shared by both activators and inhibitors of the acetylcholine receptor discussed here, thus supporting the hypothesis of their binding to a common receptor. The differences in biological activity are attributed to the effect of molecular structural factors which are not commonly included in the molecular arrangement based on the active groups of acetylcholine. The role of such factors is revealed by a study of the observed differences in the cholinergic and psychomimetic activities of related pairs of isomers and enantiomers of the molecules investigated. Structural factors which interfere with the conformational changes occurring in the receptor protein induced by an activator are characterized through differences obtained by the comparative investigation of the activities of the agonist acetate and the antagonist benzilate amino esters of quinuclidine, tropine, and pseudotropine. The same factors are shown in studies of the phencyclidine series to contribute to the antagonism to acetylcholine activity that is closely related to the psychomimetic activity of these drugs in the central nervous system. Similarly, phencyclidine derivatives in which the characteristic acetylcholine-like molecular arrangement is modified by various substitutions are shown to loose both anticholinergic and psychotropic behavior. This close correlation is supported by the identification of molecular regions which will generate the proper molecular arrangement in local anesthetics and morphine, compounds which are known to be involved in cholinergic mechanisms. Images PMID:4522291

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

PubMed Central

Gaskin, Philip LR; Toledo-Rodriguez, Maria; Alexander, Stephen PH

2016-01-01

Background: Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model. Methods: Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2–4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60–75) and drug-free hippocampal gene expression on PND 70. Results: Acute lamotrigine (10–15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia. Conclusions: Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia. PMID:27382048

Preclinical evaluation of the antipsychotic potential of the mGlu2-positive allosteric modulator JNJ-40411813

PubMed Central

Lavreysen, Hilde; Langlois, Xavier; Donck, Luc Ver; Nuñez, José María Cid; Pype, Stefan; Lütjens, Robert; Megens, Anton

2015-01-01

JNJ-40411813/ADX71149 (1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl) pyridin-2(1H)-one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5-Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent-specific metabolite. JNJ-40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4-amino-2-thiabicyclo [3.1.0] hexane-4,6-dicarboxylic acid 2,2-dioxide), the selective mGlu2 PAM JNJ-42153605 (3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ-40411813, JNJ-42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine- and scopolamine-induced but not d-amphetamine-induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine-induced hyperlocomotion. As measured by 2-deoxyglucose uptake, all compounds reversed memantine-induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5-dimethoxy-4-methylamphetamine-induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ-40411813. PMID:25692027

Anticonvulsant, anxiolytic and discriminative effects of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX).

PubMed

Swedberg, M D; Jacobsen, P; Honoré, T

1995-09-01

The anticonvulsant effects of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), phencyclidine (PCP) and diazepam against audiogenic seizures in DBA/2 mice and against seizures induced by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in NMRI mice were compared. Motor impairment was assessed in a rotarod apparatus in DBA/2 as well as NMRI mice. At 30 min after i.p. administration, NBQX was as effective as PCP and diazepam in protecting against audiogenic seizures and had a therapeutic ratio slightly higher than diazepam's and 7-fold higher than PCP's. Whereas diazepam was fully effective, NBQX and PCP were both ineffective against seizures induced by DMCM 30 min after i.p. administration. The anticonvulsant potential and motor-impairing effects of NBQX were evaluated further by the i.p. and the i.v. routes at different time points after administration. At all pretreatment intervals, NBQX protected against audiogenic seizures more potently than it produced motor impairment. NBQX administered i.p. protected against DMCM-induced seizures when given 15 min but not 5 min before testing, whereas after i.v. administration NBQX produced anticonvulsant and motor-impairing effects in the same dose range. NBQX only slightly and non-dose-dependently attenuated the discriminative effects of pentylenetetrazole in rats, showing a limited anxiolytic potential. NBQX produced no PCP-like or morphine-like discriminative effects in rats, suggesting lack of PCP or opiate-like subjective effects. These data demonstrate that NBQX has anticonvulsant effects, has limited anxiolytic effects, and does not produce subjective effects of PCP or opiate type.

Adolescent Drug Use in a Southern, Middle-Class Metropolitan High School.

ERIC Educational Resources Information Center

Chandler, Joyce; Page, Richard

1991-01-01

Examined patterns of drug use among southern, metropolitan, middle to upper-middle class high school students (n=240). Found that alcohol use was much more prevalent than was marijuana use. There was little evidence that many students had ever used cocaine in any form, depressants, phencyclidine (PCP), or lysergic acid diethylamide (LSD).(NB)

Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

PubMed Central

Moreau, J. L.; Pieri, L.; Prud'hon, B.

1989-01-01

1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061

Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

PubMed Central

Paparelli, Alessandra; Di Forti, Marta; Morrison, Paul D.; Murray, Robin M.

2010-01-01

The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia. PMID:21267359

The Use of Fry (Embalming Fluid and PCP-Laced Cigarettes or Marijuana Sticks) among Crack Cocaine Smokers

ERIC Educational Resources Information Center

Peters, Ronald J.; Williams, Mark; Ross, Michael W.; Atkinson, John; McCurdy, Sherly A.

2009-01-01

Statistics show that the prevalence of crack cocaine use and embalming fluid and phencyclidine (PCP)-laced cigarettes or marijuana sticks, commonly referred to on the street as "fry" or "wet" is a problem; however, the relationship between these substances of abuse and concurrent polydrug use is unknown. In the present study, a…

Brain catechol-o-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice

PubMed Central

Detrait, E.R.; Carr, G.V.; Ferraille, S.; Weinberger, D.R.; Lamberty, Y.

2015-01-01

The critical involvement of dopamine in cognitive processes has been well established, suggesting therapies targeting dopamine metabolism may alleviate cognitive dysfunction. COMT is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition for alleviating cognitive impairment. A brain penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine (PCP)-treated rats and COMT–Val transgenic mice. In a Novel Object Recognition (NOR) procedure, tolcapone counteracted a 24h-dependent forgetting of a familiar object and counteracted PCP-induced recognition deficits in the rats at doses ranging from 7.5 to 30 mg/kg. In contrast, entacapone, a COMT inhibitor which does not readily cross the blood-brain barrier failed to show efficacy at doses up to 30mg/kg. Tolcapone at a dose of 30 mg/kg also improved NOR performance in the transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders. PMID:26919286

Poisons Implicated In Homicidal, Suicidal And Accidental Cases In North-West Pakistan.

PubMed

Jan, Adil; Khan, Muhammad Jaffar; Humayun Khan, Muhammad Tariq; Masood Khan, Muhammad Tariq; Fatima, Sadia

2016-01-01

Pakistan has one of the highest prevalence of poisoning in the world. However, limited data exist on the frequency of poisons implicated in homicidal, suicidal, and accidental cases in North-West Pakistan (Khyber Pakhtunkhwa). This retrospective study of 353 cases and biological specimens of poisoning received at the department of Forensic medicine and toxicology, Khyber Medical College Peshawar from 13 districts of Khyber Pakhtunkhwa. Frequency of poisoning was assessed by testing each specimen for 17 different poisons. Of all the specimens, 250 (70.8%) specimens tested positive and the rest didn't show any indication of poisoning (n=103, 29.2%). The most frequent poisons detected were benzodiazepines (total n=75), organophosphates (total n=58), phencyclidine (total n=30) and morphine (total n=23). Gender had a significant association with benzodiazepines (p=0.011), tricyclic antidepressants (p=0.001), and organophosphates (p<0.001). Organophosphates were the most common cause of poisoning in females while benzodiazepines were the most common cause of poisoning in males. Poisoning by benzodiazepines, organophosphates and phencyclidine are the most common causes of intoxication in population of Khyber Pakhtunkhwa. Source of poisoning varies with gender for organophosphates, benzodiazepines and tricyclic antidepressants.

Drug binding to the acetylcholine receptor: Nitroxide analogs of phencyclidine and a local anesthetic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palma, A.L.

1988-01-01

The interaction of noncompetitive inhibitors (NCIs) with Torpedo californica native nicotinic acetylcholine receptor (nAChR) membranes was examined primarily by the technique of electron paramagnetic resonance (EPR) spectroscopy. The goal of this work being to define some of the physical characteristics for the site(s) of association between an NCI and the nAChR membrane. A nitroxide labeled analog of a quaternary amine local anesthetic, 2-(N,N-dimethyl-N-4-(2,2,6,6-tetramethylpiperidinoxyl)amino)-ethyl 4-hexyloxybenzoate iodide (C6SLMeI), displays a strongly immobilized EPR component when added to nAChR membranes in the presence of carbamylcholine (carb). To further this work, a nitroxide labeled analog of phencyclidine (PCP), a potent NCI, was synthesized. 4-phenyl-4-(1-piperidinyl)-2,2,6,6-tetramethylpiperidinoxylmore » (PPT) exhibited one-third the potency of PCP in inhibiting nAChR mediated ion flux, and from competition binding studies with ({sup 3}H)PCP displayed a K{sub D} of 0.21 {mu}M towards a carb desensitized nAChR and a K{sub 0.5} of 18 {mu}M for a resting {alpha}-bungarotoxin treated nAChR.« less

REVIEWING THE KETAMINE MODEL FOR SCHIZOPHRENIA

PubMed Central

Frohlich, Joel

2014-01-01

The observation that antagonists of the N-methyl-D-aspartate glutamate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory -aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal aberrations of NMDAR might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia. PMID:24257811

Mitochondrial impairment, apoptosis and autophagy in a rat brain as immediate and long-term effects of perinatal phencyclidine treatment - influence of restraint stress.

PubMed

Jevtić, Gordana; Nikolić, Tatjana; Mirčić, Aleksandar; Stojković, Tihomir; Velimirović, Milica; Trajković, Vladimir; Marković, Ivanka; Trbovich, Alexander M; Radonjić, Nevena V; Petronijević, Nataša D

2016-04-03

Phencyclidine (PCP) acts as a non-competitive antagonist of glutamatergic N-methyl-d-aspartate receptor. Its perinatal administration to rats causes pathophysiological changes that mimick some pathological features of schizophrenia (SCH). Numerous data indicate that abnormalities in mitochondrial structure and function could be associated with the development of SCH. Mitochondrial dysfunction could result in the activation of apoptosis and/or autophagy. The aim of this study was to assess immediate and long-term effects of perinatal PCP administration and acute restraint stress on the activity of respiratory chain enzymes, expression of apoptosis and autophagy markers and ultrastructural changes in the cortex and hippocampus of the rat brain. Six groups of rats were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal days (P), with either PCP (10mg/kg) or saline (0.9% NaCl). One NaCl and one PCP group were sacrificed on P13, while other two NaCl and PCP groups were sacrificed on P70. The remaining two NaCl and PCP groups were subjected to 1h restraint stress prior sacrifice on P70. Activities of respiratory chain enzymes were assessed spectrophotometrically. Expression of caspase 3 and AIF as markers of apoptosis and Beclin 1, p62 and LC3, as autophagy markers, was assessed by Western blot. Morphological changes of cortical and hippocampal ultrastructure were determined by transmission electron microscopy. Immediate effects of perinatal PCP administration at P13 were increased activities of complex I in the hippocampus and cytochrome c oxidase (COX) in the cortex and hippocampus implying mitochondrial dysfunction. These changes were followed by increased expression of apoptotic markers. However the measurement of autophagy markers at this time point has revealed decrease of this process in cortex and the absence of changes in hippocampus. At P70 the activity of complex I was unchanged while COX activity was significantly decreased in cortex and increased in the hippocampus. Expressions of apoptotic markers were still significantly higher in PCP perinatally treated rats in all investigated structures, but the changes of autophagy markers have indicated increased level of autophagy also in both structures. Restraint stress on P70 has caused increase of COX activity both in NaCl and PCP perinatally treated rats, but this increase was lower in PCP group. Also, restraint stress resulted in decrease of apoptotic and increase of autophagy processes especially in the hippocampus of PCP perinatally treated group. The presence of apoptosis and autophagy in the brain was confirmed by transmission electron microscopy. In this study we have demonstrated for the first time the presence of autophagy in PCP model of SCH. Also, we have shown increased sensitivity of PCP perinatally treated rats to restraint stress, manifested in alterations of apoptotic and autophagy markers. The future studies are necessary to elucidate the role of mitochondria in the pathophysiology of SCH and putative significance for development of novel therapeutic strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

Substance Testing in the Fire Service: Making Public Safety a Matter of National Policy

DTIC Science & Technology

2014-03-01

25). Leshner (1999) submits that virtually every addictive substance—be it cocaine, marijuana , methamphetamine, heroin, or nicotine— appears to...safety sensitive. The DOT test panel tests for five classifications of drugs: amphetamines, cocaine, marijuana , opiates, and phencyclidine. When the...methods are laws, political/socio-cultural, pricing of services, and individual fire departments. Marijuana has been legalized in a number of states

Personnel-General: Army Substance Abuse Program Civilian Services

DTIC Science & Technology

2001-10-15

destroyed. Additional reproduction and distribution of completed records is prohibited. c. SECTION I. IDENTIFICATION. (1) Block I. Date of Report. Enter...AMPHETAMINE B BARBITUATES C COCAINE H HALLUCINOGENS (LSD) M METHAQUALONE, SEDATIVE, HYPNOTIC , OR ANXIOLYTIC O OPIATES P PHENCYCLIDINE (PCP) T CANNABIS...Table 5–6 Codes for TABLE F (T-DIAG-CODE) Code Rejection Reason 30390 ALCOHOL DEPENDENCE 30400 OPIOID DEPENDENCE 30410 SEDATIVE, HYPNOTIC , OR ANXIOLYTIC

Differential effects of acute amphetamine and phencyclidine treatment and withdrawal from repeated amphetamine or phencyclidine treatment on social interaction and social memory in rats.

PubMed

Li, Ming; He, Wei; Munro, Rebecca

2012-06-01

Although animal models based on amphetamine (AMPH) or phencyclidine (PCP) treatment have been used extensively to study the neurobiological and behavioral characteristics of schizophrenia, there are conflicting reports regarding their validity in modeling the negative symptoms and cognitive deficits of schizophrenia. The present study examined how acute AMPH or PCP treatment (Experiment 1) and withdrawal from repeated AMPH treatment (Experiment 2) or PCP treatment (Experiment 3) affects social behavior and social recognition memory in male Sprague-Dawley rats. Each subject was tested on two consecutive days. On the first day, the rats were tested four times (5 min/each) at 10-min intervals with the same partner rat (termed "AAAA" day). One day later, the rats were tested with the previous partner in the first three sessions and with a new partner rat in the final session (termed "AAAB" day). The results show that acute AMPH treatment (1.5 mg/kg, sc) significantly reduced the time spent on social interaction, but did not affect social recognition on the first day. Acute AMPH only disrupted social recognition on the second day of drug testing. In contrast, acute PCP treatment (2.0 mg/kg, sc) had no effect on time spent on social interaction, but did significantly disrupt social recognition on both days. Withdrawal from repeated AMPH (3.0 mg/kg/day for 7 days, ip) or PCP (5.0 mg/kg/twice daily for 7 days, ip) treatment did not affect social interaction or social recognition, indicating a lack of long-term detrimental effect of repeated AMPH or PCP treatment. These results suggest that acute AMPH treatment at a low dose (1.5 mg/kg) may be useful in modeling social withdrawal symptoms of schizophrenia, whereas acute PCP treatment at a similar dose range (2.0 mg/kg) may be useful in modeling the social cognitive deficit of schizophrenia. © 2012 The Institute of Psychology, Chinese Academy of Sciences and Blackwell Publishing Asia Pty Ltd.

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward.

PubMed

Carroll, Marilyn E; Collins, Molly; Kohl, Emily A; Johnson, Seth; Dougen, Ben

2016-08-01

In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. Cocaine deliveries were similar in males and females in the females' luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females' follicular and luteal phases. Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females' follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine's rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females' luteal phase.

Role of Major NMDA or AMPA Receptor Subunits in MK-801 Potentiation of Ethanol Intoxication

PubMed Central

Palachick, Benjamin; Chen, Yi-Chyan; Enoch, Abigail J.; Karlsson, Rose-Marie; Mishina, Masayoshi; Holmes, Andrew

2008-01-01

Background The glutamate system plays a major role in mediating EtOH’s effects on brain and behavior, and is implicated in the pathophysiology of alcohol-related disorders. N-methyl-D-aspartate receptor (NMDAR) antagonists such as MK-801 (dizocilpine) interact with EtOH at the behavioral level, but the molecular basis of this interaction is unclear. Methods We first characterized the effects of MK-801 treatment on responses to the ataxic (accelerating rotarod), hypothermic and sedative/hypnotic effects of acute EtOH administration in C57BL/6J and 129/SvImJ inbred mice. Effects of another NMDAR antagonist, phencyclidine, on EtOH-induced sedation/hypnosis were also assessed. Gene knockout of the NMDAR subunit NR2A or L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate GluR1 or pharmacological antagonism of the NMDAR subunit NR2B (via Ro 25-6981) was employed to examine whether inactivating any one of these glutamate signaling molecules modified MK-801’s effect on EtOH-related behaviors. Results MK-801 markedly potentiated the ataxic effects of 1.75 g/kg EtOH and the sedative/hypnotic effects of 3.0 g/kg EtOH, but not the hypothermic effects of 3.0 g/kg EtOH, in C57BL/6J and 129/SvImJ mice. Phencyclidine potentiated EtOH-induced sedation/hypnosis in both inbred strains. Neither NR2A nor GluR1 KO significantly altered basal EtOH-induced ataxia, hypothermia, or sedation/hypnosis. Ro 25-6981 modestly increased EtOH-induced sedation/hypnosis. The ability of MK-801 to potentiate EtOH-induced ataxia and sedation/hypnosis was unaffected by GluR1 KO or NR2B antagonism. NR2A KO partially reduced MK-801 + EtOH-induced sedation/hypnosis, but not ataxia or hypothermia. Conclusions Data confirm a robust and response-specific potentiating effect of MK-801 on sensitivity to EtOH’s intoxicating effects. Inactivation of three major components of glutamate signaling had no or only partial impact on the ability of MK-801 to potentiate behavioral sensitivity to EtOH. Further work to elucidate the mechanisms underlying NMDAR × EtOH interactions could ultimately provide novel insight into the role of NMDARs in alcoholism and its treatment. PMID:18565157

An Ion-Selective Electrode for the Determination of Phencyclidine (PCP).

DTIC Science & Technology

1980-08-06

as an indicator_ ectrode in potentiometric titration of PCPA at concentrations DD 1473 EDITION or I Nov soIS OSSOOL TC SEPURqITY CLAWSFICATION Of...and ISE detection limits determined as described previous (25). The PCP electrode was used as the indicator electrode in potentiometric titrations of...was standardized by potentiometric titration with a dodecyltrimethyl- ammonium bromide (DoTAB) solution using a DoTA+ ISE (25) as the indicator

Novel Anticonvulsant Analogs of Dextromethorphan: Improved Efficacy, Potency, Duration and Side-Effect Profile

DTIC Science & Technology

1994-02-01

dextromethorphan (014, [+J-3-aethyl-l7-methylmorphinan) may be, in part, due to its ____________________metabolism to the PCP-like compound... Dextromethorphan : Improved Efficacy, Potency, Duration and Side-Effect Profile1 FRANK C. TORTELLA, LYDIA ROBLES, JEFFREY M. WITKIN and AMY HAUCK NEWMAN... dextromethorphan ; NMDA, N-methyl-D-aspartate; PCP, phencyclidine hydrochloride; DX, dextrorphan; AHN649, [(+)-3- amino-1 7-methylmorphinan]; AHN1 -036

Treatment of PCP addiction and PCP addiction-related behavior

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dewey, Stephen L.; Brodie, Jonathan D.; Ashby, Jr., Charles R.

2002-01-01

The present invention provides a method for changing addiction-related behavior of a mammal suffering from addiction to phencyclidine (PCP). The method includes administering to the mammal an effective amount of gamma vinylGABA (GVG) or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate behavior associated with craving or use of PCP.

Brief exposure to methamphetamine (METH) and phencyclidine (PCP) during late development leads to long-term learning deficits in rats.

PubMed

White, Ilsun M; Minamoto, Takehiro; Odell, Joseph R; Mayhorn, Joseph; White, Wesley

2009-04-17

Exposure to methamphetamine (METH) and phencyclidine (PCP) during early development is thought to produce later behavioral deficits. We postulated that exposure to METH and PCP during later development would produce similar behavioral deficits, particularly learning deficits in adulthood. Wistar rats were treated with METH (9 mg/kg), PCP (9 mg/kg), or saline during later development, postnatal days (PD) 50-51, and subsequent behavioral changes were examined including: locomotor activity during the acute drug state (PD 50-51) and the post-drug phase (PD 50-80); social interaction on PD 54-80; and spatial discrimination and reversal in adulthood (after PD 90). METH and PCP differentially affected locomotion during the acute state, but not during the post-drug phase. METH decreased social interaction throughout tests two weeks after drug treatment, whereas PCP decreased social interaction only during the first 8 min of tests. Neither METH nor PCP impaired initial acquisition of spatial discrimination. However, reversal was significantly impaired by PCP, whereas METH produced a mild deficit, compared to controls. Our data provide evidence that exposure to PCP and METH during later development lead to enduring cognitive deficits in adulthood. Selective impairment of reversal may reflect neurological damage in the prefrontal cortex due to early exposure to drugs.

N-(3-azidophenyl)-N-methyl-N'-([4-1H]- and [4-3H]-1-naphthyl)guanidine. A potent and selective ligand designed as a photoaffinity label for the phencyclidine site of the N-methyl-D-aspartate receptor.

PubMed

Gee, K R; Durant, G J; Holmes, D L; Magar, S S; Weber, E; Wong, S T; Keana, J F

1993-01-01

A novel radiolabeled photoaffinity ligand has been synthesized for the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor. N-(3-Azidophenyl)-N-methyl-N'-([4-3H]-1-naphthyl)guanidine (13) was prepared with a specific activity of 25 Ci/mmol by diazotization of N-(3-aminophenyl)-N-methyl-N'-([4-3H]-1-naphthyl)guanidine (12) followed by treatment with sodium azide. Guanidine 12 was obtained by catalytic tritiation of N-(4-bromo-1-naphthyl)-N'-methyl-N'-(3-nitrophenyl)guanidine (11). The nontritiated analog 5 of 13 was prepared beginning with N-methyl-N'-1-naphthyl-N-(3-nitrophenyl)guanidine (9). The guanidines 9 and 11 were prepared in moderate yield by the aluminum chloride-catalyzed reaction of N-methyl-3-nitroaniline hydrochloride with 1-naphthylcyanamide and 4-bromo-1-naphthylcyanamide, respectively. Azide 5 showed high selectivity and affinity (IC50 = 100 nM vs [3H]MK801; 3000 nM vs [3H]ditolylguanidine) for the PCP site of the NMDA receptor in guinea pig brain homogenate. Photolabeling experiments with 13, however, failed to radiolabel a significant amount of receptor polypeptide.

Phencyclidine and violence: clinical and legal issues.

PubMed

Brecher, M; Wang, B W; Wong, H; Morgan, J P

1988-12-01

Phencyclidine (PCP) abuse has diminished since PCP's intrusion into American culture in the late 1970s. One of its legacies is the assumption that it provokes violent behavior in humans with predictable regularity. This assumption is so accepted that ingestion of the drug both accidentally and knowingly prior to committing a crime has been used as a defense in criminal trials. We reviewed 81 clinical reports of toxicity in humans published chiefly in North American medical journals. We searched for descriptions of violent behavior in these reports and subjected them to the following questions: (1) Was the violent behavior corroborated or only self-reported? (2) Was the presence of PCP confirmed by analysis of bodily fluids or postmortem tissue? (3) Was the presence of other drugs excluded by similar analysis of bodily fluids? We had planned to examine the reports to see whether clinicians sought evidence of previous violent behavior, but such an inquiry was rarely conducted. Of the hundreds of patients described, only three satisfied these criteria. Further, some of the papers offered evidence that reports of violence were exaggerated. These findings plus the pre-1970 prospective evaluation of thousands of patients with PCP, in which violence was never reported, led us to conclude that clinical and forensic assumptions about PCP and violence are not warranted.

Solubilization of phencyclidine receptors from rat cerebral cortex in an active ligand binding site

DOE Office of Scientific and Technical Information (OSTI.GOV)

McVittie, L.D.; Sibley, D.R.

1989-01-01

A phencyclidine (PCP) receptor binding site has been solubilized in an active ligand-binding state from rat cerebral cortical membranes with sodium deoxycholate. Optimal receptor solubilization occurs at a detergent/protein ratio of 0.5 (w/w); for 5 mg protein/ml solubilized with 0.25% sodium deoxycholate, about 60% of the protein and 25% of the receptor is solubilized. Specific binding of either (/sup 3/H)-N-(1-(2-thienyl)cyclohexyl)piperidine ((/sup 3/H)TCP) or (/sup 3/H)MK-801 is measurable by filtration through Sephadex G-50 columns or glass fiber filters; more than 60% of the binding activity is stable after 48 h at 4/degrees/C. In the presence of detergent, (/sup 3/H)TCP binding exhibitsmore » a K/sub d/ of 250 nM, a B/sub max/ of 0.56 pmol/mg protein, and a pharmacological profile consistent with that of the membrane-bound PCP receptor, although most drugs bind with affinities 2 to 8 fold lower than in membranes. Upon reduction of detergent concentration, binding parameters approximate those for the membrane-bound receptor (/sup 3/H)TCP binding: K/sub d/ = 48 nM, M/sub max/ = 1.13 pmol/mg protein.« less

Prenatal exposure to phencyclidine produces abnormal behaviour and NMDA receptor expression in postpubertal mice.

PubMed

Lu, Lingling; Mamiya, Takayoshi; Lu, Ping; Toriumi, Kazuya; Mouri, Akihiro; Hiramatsu, Masayuki; Kim, Hyoung-Chun; Zou, Li-Bo; Nagai, Taku; Nabeshima, Toshitaka

2010-08-01

Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans. Previous studies have reported that perinatal treatment with phencyclidine (PCP) impairs the development of neuronal systems and induces schizophrenia-like behaviour. However, the adverse effects of prenatal exposure to PCP on behaviour and the function of NMDA receptors are not well understood. This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk. Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice. It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life.

Pyrolytic fate of piperidinocyclohexanecarbonitrile, a contaminant of phencyclidine, during smoking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lue, L.P.; Scimeca, J.A.; Thomas, B.F.

The pyrolysis products of 1-(1-piperidino)cyclo-hexanecarbonitrile (PCC), the major contaminant of illicit phencyclidine (PCP), have not been previously reported. In order to quantify PCC in mainstream smoke as well as to identify the pyrolysis products, (/sup 3/H)piperidino-(/sup 14/C)cyano-PCC was synthesized. Marijuana placebo cigarettes were impregnated with this double-labeled PCC and burned with an apparatus that simulated smoking. The mainstream smoke was passed through a series of traps containing glass wool, H/sub 2/SO/sub 4/, or NaOH. Approximately 75% of the /sup 3/H was collected in these traps, and 46, 11, and 5% of the /sup 14/C was found in the glass wool,more » H/sub 2/SO/sub 4/, and NaOH traps, respectively. Contents of the traps were analyzed by GC/MS. The glass wool trap contained 1-(1-piperidino)-1-cyclo-hexene, PCC, piperidine, and N-acetylpiperidine, and cyanide ion was detected in all three traps. Approximately 47% of the PCC was found intact in mainstream smoke. Approximately 58% was cleaved to form cyanide and 1-(1-piperidino)-1-cyclohexene. The latter was further broken down to cyclohexanone (which represented 21% of the starting material), piperidine (29%), and N-acetylpiperidine (7%), and about 2% remained intact.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pitts, F.N. Jr.; Allen, R.E.; Aniline, O.

By utilizing a glass capillary gas chromatographic nitrogen detector (GC2-N) method specific for phencyclidine (PCP) and sensitive to pg/mL in blood or urine samples, we have demonstrated occupational intoxication of law enforcement personnel charged with handling confiscated illegal PCP preparations. Further, we have demonstrated persistence of PCP in blood and urine for at least 6 months after the last known occupational exposure in one officer. Some aspects of the PCP problem are outlined, and possible mechanisms of the occupational intoxication are discussed.

An Analysis of the Effectiveness of the Air Force Drug Testing Program and Four Potential Modifications

DTIC Science & Technology

1993-09-01

attempted to control substance abuse. In the 1920’s and 30’s, marijuana was commonly used as a substitute for alcohol during prohibition (1:4-7). In...discovered D-lysergic acia tiiethylamide (LSD), methaqualone (quaalude), and phencyclidine (PCP) joined heroin, amphetamines, and marijuana as drugs abused...themselves in Southeast Asia where drugs were plentiful and cheap. The most commonly used drugs were heroin and marijuana . Initially, the DOD policy

Ginsenoside Re protects against phencyclidine-induced behavioral changes and mitochondrial dysfunction via interactive modulation of glutathione peroxidase-1 and NADPH oxidase in the dorsolateral cortex of mice.

PubMed

Tran, The-Vinh; Shin, Eun-Joo; Dang, Duy-Khanh; Ko, Sung Kwon; Jeong, Ji Hoon; Nah, Seung-Yeol; Jang, Choon-Gon; Lee, Yu Jeung; Toriumi, Kazuya; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2017-12-01

We investigated whether ginsenoside Re (Re) modulates phencyclidine (PCP)-induced sociability deficits and recognition memory impairments to extend our recent finding. We examined the role of GPx-1 gene in the pharmacological activity of Re against mitochondrial dysfunction induced by PCP in the dorsolateral cortex of mice. Since mitochondrial oxidative stress activates NADPH oxidase (PHOX), we applied PHOX inhibitor apocynin for evaluating interactive modulation between GPx-1 and PHOX against PCP neurotoxicity. Sociability deficits and recognition memory impairments induced by PCP were more pronounced in GPx-1 knockout (KO) than in wild type (WT) mice. PCP-induced mitochondrial oxidative stress, mitochondrial dysfunction, and membrane translocation of p47phox were more evident in GPx-1 KO than in WT. Re treatment significantly attenuated PCP-induced neurotoxic changes. Re also significantly attenuated PCP-induced sociability deficits and recognition memory impairments. The attenuation by Re was comparable to that by apocynin. The attenuation was more obvious in GPx-1 KO than in WT. Importantly, apocynin did not show any additional positive effects on the neuroprotective activity of Re, indicating that PHOX is a molecular target for therapeutic activity of Re. Our results suggest that Re requires interactive modulation between GPx activity and PHOX (p47phox) to exhibit neuroprotective potentials against PCP insult. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neonatal handling prevents the effects of phencyclidine in an animal model of negative symptoms of schizophrenia.

PubMed

Tejedor-Real, Purificación; Sahagún, Mar; Biguet, Nicole Faucon; Mallet, Jacques

2007-04-01

Environmental factors during the neonatal period have long-lasting effects on the brain. Neonatal handling, an early mild stress, enhances the ability to cope with stress in adult rats. In humans, inappropriate stress responses increase the risk of schizophrenia in genetically predisposed individuals. We studied the effect of neonatal handling on the phencyclidine (PCP)-induced immobility time of rats in the forced swimming test (FST, an animal model of negative symptoms of schizophrenia) and on plasma adrenocorticotropic hormone (ACTH) as a measure of hypothalamic-pituitary-adrenal axis (HPA) reactivity. Pups were removed from their mothers 15 min/21 days after birth. Postnatal day 65: animals were submitted to restraint stress. Postnatal day 75: after PCP treatment (5 mg/kg/5 days) animals were submitted to the FST. Neonatal handling reduced HPA reactivity to passive stress (restraint) but not to active coping stress (forced swimming). Immobilization time was significantly lower in saline- and PCP-treated, handled animals than in non-handled ones. Handling prevented the ACTH increase induced by PCP that was observed in the non-handled rats after FST. First, neonatal handling protects animals from acquiring the schizophrenic-like behavior provoked by sub-chronic PCP treatment, which was associated with a reduced HPA activity. Second, the beneficial properties of handling in stress responses seem to depend on the type of stress.

Modelling the cognitive and neuropathological features of schizophrenia with phencyclidine.

PubMed

Reynolds, Gavin P; Neill, Joanna C

2016-11-01

Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding protein found in GABA interneurons known to be reduced in schizophrenia patients, in conjunction with a deficit in reversal learning in an animal model for schizophrenia. This publication resulted from common research interests: Reynolds in the neurotransmitter pathology of schizophrenia, and Neill in developing animal models for schizophrenia symptomatology. The animal model, using a sub-chronic dosing regimen (sc) with the non-competitive NMDA receptor antagonist PCP (phencyclidine), evolved from previous work in rats (for PCP) and primates (for cognition). The hypothesis of a PV deficit came from emerging evidence for a GABAergic dysfunction in schizophrenia, in particular a deficit in PV-containing GABA interneurons. Since this original publication, a PV deficit has been identified in other animal models for schizophrenia, and the PV field has expanded considerably. This includes mechanistic work attempting to identify the link between oxidative stress and GABAergic dysfunction using this scPCP model, and assessment of the potential of the PV neuron as a target for new antipsychotic drugs. The latter has included development of a molecule targeting KV3.1 channels located on PV-containing GABA interneurons which can restore both PV expression and cognitive deficits in the scPCP model. © The Author(s) 2016.

Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex.

PubMed

Toriumi, Kazuya; Oki, Mika; Muto, Eriko; Tanaka, Junko; Mouri, Akihiro; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2016-06-01

We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.

Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment.

PubMed

Mouri, Akihiro; Noda, Yukihiro; Enomoto, Takeshi; Nabeshima, Toshitaka

2007-01-01

In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.

Interaction of the phencyclidine model of schizophrenia and nicotine on total and categorized ultrasonic vocalizations in rats

PubMed Central

Swalve, Natashia; Mulholland, Michele M.; Schulz, Tiffany D.; Li, Ming

2015-01-01

Patients with schizophrenia smoke cigarettes at a higher rate than the general population. We hypothesized that a factor in this comorbidity is sensitivity to the reinforcing and reinforcement-enhancement effects of nicotine. Phencyclidine (PCP) was used to model behavioral changes resembling negative symptoms of schizophrenia in rats. USVs in rats have been used to measure emotional states, with 50 kHz USVs indicating positive states and 22 kHz indicating negative. Total and categorized numbers of 22 and 50 kHz ultrasonic vocalizations (USVs) and USVs during a visual stimulus (e.g. a potential measure of reinforcement-enhancement) were examined in rats following .injection ofh PCP (2.0 mg/kg), and/or nicotine (0.2 or 0.4 mg/kg) daily for 7 days. PCP was then discontinued and all rats received nicotine (0.2 mg/kg and 0.4 mg/kg) and PCP (2.0 mg/kg) on 3 challenge days. PCP acutely decreased 50 kHz vocalizations while repeated nicotine potentiated rates of vocalizations, with similar patterns during light presentations. Rats in the PCP and nicotine combination groups made more 50 kHz vocalizations compared to control groups on challenge days. We conclude that PCP may produce a reward deficit that is shown by decreased 50 kHz USVs, and behaviors post-PCP exposure may best model the comorbidity between schizophrenia and nicotine. PMID:26479849

Properties of the cromakalim-induced potassium conductance in smooth muscle cells isolated from the rabbit portal vein.

PubMed Central

Beech, D. J.; Bolton, T. B.

1989-01-01

1. Single smooth muscle cells were isolated freshly from the rabbit portal vein and membrane currents were recorded by the whole-cell or excised patch configurations of the patch-clamp technique at room temperature. 2. Cromakalim (Ckm, 10 microM) induced a potassium current (ICkm) that showed no pronounced voltage-dependence and had low current noise. 3. This current, ICkm, was inhibited by (in order of potency): phencyclidine greater than quinidine greater than 4-aminopyridine greater than tetraethylammonium ions (TEA). These drugs inhibited the delayed rectifier current, IdK, which is activated by depolarization of the cell, with the same order of potency. 4. Large conductance calcium-activated potassium channels (LKCa) in isolated membrane patches were blocked by (in order of potency) quinidine greater than TEA approximately phencyclidine. 4-Aminopyridine was ineffective. A similar order of potency was found for block of spontaneous transient outward currents thought to represent bursts of openings of LKCa channels. 5. The low current noise of ICkm at positive potentials, and its susceptibility to inhibitors indicated that it was not carried by LKCa channels, and that it may be carried by channels which underlie IdK. It was observed that when ICkm was activated, IdK was reduced. However, in two experiments, ICkm was much more susceptible to glibenclamide than IdK; possible reasons for this are discussed. PMID:2590772

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward

PubMed Central

Carroll, Marilyn E.; Collins, Molly; Kohl, Emily A.; Johnson, Seth; Dougen, Ben

2016-01-01

Background In previous studies female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. Objectives The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. Materials and methods Concurrent access to cocaine (0.2, 0.4 and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. Results Cocaine deliveries were similar in males and females in the females’ luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females’ follicular and luteal phases. Conclusions Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females’ follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine’s rewarding effects on male and female monkeys, and reductions in cocaine-seeking were optimal in the females’ luteal phase. PMID:27318989

JPRS Report, Latin America, Reference Aid, Glossary of Spanish and Portuguese Narcotics Terms.

DTIC Science & Technology

1989-05-04

devils, seconal, barbiturates, amphetamines, LSD a "deal"—to make a connection to obtain drugs (Ar) to deal bread, dough , money "dirty money...drug addict federal police; feds, "G" men PCP; angel dust; phencyclidine bread, dough , money weapon (Ar) a fix, a jab to inject, to shoot up...used to cut heroin); manida, mannite, milk sugar brick (usually a kilogram of hashish or marijuana) bread, dough , money money laundering to

Effect of Environmental Cues on Behavioral Efficacy of Haloperidol, Olanzapine and Clozapine in Rats

PubMed Central

Sun, Tao; Liu, Xinfeng; Li, Ming

2014-01-01

Previous studies have reported that context can powerfully modulate the inhibitory effect of an antipsychotic drug on phencyclidine (PCP)-induced hyperlocomotion (a behavioral test used to evaluate putative antipsychotic drugs). The present study investigated the experimental conditions under which environmental stimuli exert their influence through associative conditioning processes. Experiment 1 examined the extent to which prior antipsychotic treatment in the home cages affected a drug’s ability to inhibit PCP-induced hyperlocomotion in a novel motor activity test apparatus. Five days of repeated haloperidol (0.05 mg/kg, sc) and olanzapine (2.0 mg/kg, sc) treatment in the home cages still potentiated their inhibition of PCP-induced hyperlocomotion (i.e. sensitization) assessed in a new environment, whereas the clozapine (10.0 mg/kg, sc) treatment enhanced the development of clozapine tolerance, indicating a lack of environmental modulation of antipsychotic efficacy. Experiment 2 assessed the impact of different numbers of antipsychotic administrations in either the home environment or test environment (e.g. 4, 2 or 0) on a drug’s ability to inhibit PCP-induced hyperlocomotion. Repeated administration of clozapine (5.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) for 4 consecutive days, regardless of where these treatments occurred, caused a similar level of inhibition on PCP-induced hyperlocomotion. However, 4-day haloperidol (0.03 mg/kg, sc) treatment in the test apparatus caused a significant higher inhibition than 4-day home cage treatment. Thus, more exposures to the test environment under the influence of haloperidol (but not clozapine or olanzapine) cause a stronger inhibition than fewer exposures, indicating a strong environmental modulation. Collectively, these findings suggest that prior antipsychotic treatment in one environment could alter later antipsychotic-like response assessed in a different environment under certain test conditions. Therefore, whether the circumstances surrounding antipsychotic drug administration exert a powerful control of the expression of antipsychotic-like efficacy is dependent on specific experimental and drug treatment factors. PMID:24949569

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia.

PubMed

Rajagopal, Lakshmi; Kwon, Sunoh; Huang, Mei; Michael, Eric; Bhat, Laxminarayan; Cantillon, Marc; Meltzer, Herbert Y

2017-08-14

Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D 2 , D 3 , D 4 , serotonin (5-HT) 1A , and 5-HT 2A receptors (Rs), full agonism at α 4 β 2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT 2B , 5-HT 6 , and 5-HT 7 Rs. Most atypical APDs are 5-HT 2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT 7 R antagonist, a 5-HT 1B R antagonist, a 5-HT 2A R inverse agonist, or an α 4 β 2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT 1A R, a D 4 R, antagonist, but not an α 4 β 2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia. Copyright © 2017. Published by Elsevier B.V.

Is immunotherapy an opportunity for effective treatment of drug addiction?

PubMed

Zalewska-Kaszubska, Jadwiga

2015-11-27

Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

A simple validated multi-analyte method for detecting drugs in oral fluid by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

PubMed

Zheng, Yufang; Sparve, Erik; Bergström, Mats

2018-06-01

A UPLC-MS/MS method was developed to identify and quantitate 37 commonly abused drugs in oral fluid. Drugs of interest included amphetamines, benzodiazepines, cocaine, opiates, opioids, phencyclidine and tetrahydrocannabinol. Sample preparation and extraction are simple, and analysis times short. Validation showed satisfactory performance at relevant concentrations. The possibility of contaminated samples as well as the interpretation in relation to well-knows matrices, such as urine, will demand further study. Copyright © 2017 John Wiley & Sons, Ltd.

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

PubMed

Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

2014-03-01

Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. © 2013 International Society for Neurochemistry.

Modafinil Reverses Phencyclidine-Induced Deficits in Cognitive Flexibility, Cerebral Metabolism, and Functional Brain Connectivity

PubMed Central

Dawson, Neil; Thompson, Rhiannon J.; McVie, Allan; Thomson, David M.; Morris, Brian J.; Pratt, Judith A.

2012-01-01

Objective: In the present study, we employ mathematical modeling (partial least squares regression, PLSR) to elucidate the functional connectivity signatures of discrete brain regions in order to identify the functional networks subserving PCP-induced disruption of distinct cognitive functions and their restoration by the procognitive drug modafinil. Methods: We examine the functional connectivity signatures of discrete brain regions that show overt alterations in metabolism, as measured by semiquantitative 2-deoxyglucose autoradiography, in an animal model (subchronic phencyclidine [PCP] treatment), which shows cognitive inflexibility with relevance to the cognitive deficits seen in schizophrenia. Results: We identify the specific components of functional connectivity that contribute to the rescue of this cognitive inflexibility and to the restoration of overt cerebral metabolism by modafinil. We demonstrate that modafinil reversed both the PCP-induced deficit in the ability to switch attentional set and the PCP-induced hypometabolism in the prefrontal (anterior prelimbic) and retrosplenial cortices. Furthermore, modafinil selectively enhanced metabolism in the medial prelimbic cortex. The functional connectivity signatures of these regions identified a unifying functional subsystem underlying the influence of modafinil on cerebral metabolism and cognitive flexibility that included the nucleus accumbens core and locus coeruleus. In addition, these functional connectivity signatures identified coupling events specific to each brain region, which relate to known anatomical connectivity. Conclusions: These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction. PMID:20810469

Examining the Reinforcement-Enhancement Effects of Phencyclidine and Its Interactions with Nicotine on Lever-Pressing for a Visual Stimulus

PubMed Central

Swalve, Natashia; Barrett, Scott T.; Bevins, Rick A.; Li, Ming

2015-01-01

Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement-enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: 1) it produces discrepant results on overall reward, similar to that seen with nicotine and 2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0 mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement-enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances. PMID:26026783

Effects of hypoxia-ischemia and MK-801 treatment on the binding of a phencyclidine analogue in the developing rat brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silverstein, F.S.; McDonald, J.W. III; Bommarito, M.

1990-02-01

The phencyclidine analogue ({sup 3}H)(1-(2-thienyl)cyclohexyl)piperidine ({sup 3}H-TCP) binds to the ion channel associated with the N-methyl-D-aspartate receptor channel complex. In vitro autoradiography indicates that the distribution of {sup 3}H-TCP binding in brain closely parallels that of ({sup 3}H)glutamate binding to the N-methyl-D-aspartate receptor. In nine 7-day-old rats, an acute focal hypoxic-ischemic insult produced by unilateral carotid artery ligation and subsequent exposure to 8% oxygen acutely reduced {sup 3}H-TCP binding ipsilateral to the ligation by 30% in the CA1, by 27% in the CA3, by 26% in the dentate gyrus, and by 17% in the striatum compared with values from themore » contralateral hemisphere. In 10 littermates that received 1 mg/kg of the neuroprotective noncompetitive N-methyl-D-aspartate antagonist MK-801 immediately before hypoxic exposure, the regional distribution of {sup 3}H-TCP binding in hypoxic-ischemic brain was relatively preserved and there were no interhemispheric asymmetries in {sup 3}H-TCP binding densities. In addition, in three unoperated rats decapitated 24 hours after MK-801 treatment, {sup 3}H-TCP binding was reduced by 15-35%; similar bilateral suppression of {sup 3}H-TCP binding was detected in MK-801-treated ligates. Our data indicate that {sup 3}H-TCP autoradiography can be used to assay the efficacy of neuroprotective agents in this experimental model of perinatal stroke.« less

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

PubMed Central

Wesseling, Hendrik; Chan, Man K; Tsang, T M; Ernst, Agnes; Peters, Fabian; Guest, Paul C; Holmes, Elaine; Bahn, Sabine

2013-01-01

Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic- and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca2+ signaling (Ca2+/calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca2+ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ. PMID:23942359

Phencyclidine-induced Loss of Asymmetric Spine Synapses in Rodent Prefrontal Cortex is Reversed by Acute and Chronic Treatment with Olanzapine

PubMed Central

Elsworth, John D; Morrow, Bret A; Hajszan, Tibor; Leranth, Csaba; Roth, Robert H

2011-01-01

Enduring cognitive deficits exist in schizophrenic patients, long-term abusers of phencyclidine (PCP), as well as in animal PCP models of schizophrenia. It has been suggested that cognitive performance and memory processes are coupled with remodeling of pyramidal dendritic spine synapses in prefrontal cortex (PFC), and that reduced spine density and number of spine synapses in the medial PFC of PCP-treated rats may potentially underlie, at least partially, the cognitive dysfunction previously observed in this animal model. The present data show that the decrease in number of asymmetric (excitatory) spine synapses in layer II/III of PFC, previously noted at 1-week post PCP treatment also occurs, to a lesser degree, in layer V. The decrease in the number of spine synapses in layer II/III was sustained and persisted for at least 4 weeks, paralleling the observed cognitive deficits. Both acute and chronic treatment with the atypical antipsychotic drug, olanzapine, starting at 1 week after PCP treatment at doses that restore cognitive function, reversed the asymmetric spine synapse loss in PFC of PCP-treated rats. Olanzapine had no significant effect on spine synapse number in saline-treated controls. These studies demonstrate that the effect of PCP on asymmetric spine synapse number in PFC lasts at least 4 weeks in this model. This spine synapse loss in PFC is reversed by acute treatment with olanzapine, and this reversal is maintained by chronic oral treatment, paralleling the time course of the restoration of the dopamine deficit, and normalization of cognitive function produced by olanzapine. PMID:21677652

Clinical physiology and mechanism of dizocilpine (MK-801)

PubMed Central

Somanathan, Ratnasamy

2010-01-01

Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3′-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and anti-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties. PMID:20716924

Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity.

PubMed

Kovacic, Peter; Somanathan, Ratnasamy

2010-01-01

Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3'-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and ant-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties.

Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

PubMed Central

Chen, Li; Lodge, Daniel J

2015-01-01

Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Methods: Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID:25539511

Comparison of pro-amnesic efficacy of scopolamine, biperiden, and phencyclidine by using passive avoidance task in CD-1 mice.

PubMed

Malikowska, Natalia; Sałat, Kinga; Podkowa, Adrian

2017-07-01

Memory disorders accompany numerous diseases and therapies, and this is becoming a growing medical issue worldwide. Currently, various animal models of memory impairments are available; however, many of them require high financial outlay and/or are time-consuming. A simple way to achieve an efficient behavioral model of cognitive disorders is to inject defined drug that has pro-amnesic properties. Since the involvement of cholinergic and glutamatergic neurotransmission in cognition is well established, the utilization of a nonselective muscarinic receptor antagonist, scopolamine (SCOP), a selective M1 muscarinic receptor antagonist, biperiden (BIP), and a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP) seems to be reliable tools to induce amnesia. As the determination of their effective doses remains vague and the active doses vary significantly in laboratory settings and in mouse species being tested, the aim of this study was to compare these three models of amnesia in CD-1 mice. Male Swiss Albino mice were used in passive avoidance (PA) test. All the compounds were administered intraperitoneally (ip) at doses 1mg/kg, 5mg/kg, and 10mg/kg (SCOP and BIP), and 1mg/kg, 3mg/kg, and 6mg/kg (PCP). In the retention trial of the PA task, SCOP and PCP led to the reduction of step-through latency at all the tested doses as compared to control, but BIP was effective only at the dose of 10mg/kg. This study revealed the effectiveness of SCOP, PCP, and BIP as tools to induce amnesia, with the PCP model being the most efficacious and SCOP being the only model that demonstrates a clear dose-response relationship. Copyright © 2017. Published by Elsevier Inc.

Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC.

PubMed

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-02-01

Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs.

PubMed

Riga, Maurizio S; Soria, Guadalupe; Tudela, Raúl; Artigas, Francesc; Celada, Pau

2014-08-01

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (-31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

Examining the reinforcement-enhancement effects of phencyclidine and its interactions with nicotine on lever-pressing for a visual stimulus.

PubMed

Swalve, Natashia; Barrett, Scott T; Bevins, Rick A; Li, Ming

2015-09-15

Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement-enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: (1) it produces discrepant results on overall reward, similar to that seen with nicotine and (2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement-enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances. Copyright © 2015 Elsevier B.V. All rights reserved.

The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia.

PubMed

Janhunen, Sanna K; Svärd, Heta; Talpos, John; Kumar, Gaurav; Steckler, Thomas; Plath, Niels; Lerdrup, Linda; Ruby, Trine; Haman, Marie; Wyler, Roger; Ballard, Theresa M

2015-11-01

Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals. The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks. Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination. Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation. The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.

Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

PubMed Central

Suemaru, Katsuya; Yasuda, Kayo; Umeda, Kenta; Araki, Hiroaki; Shibata, Kazuhiko; Choshi, Tominari; Hibino, Satoshi; Gomita, Yutaka

2004-01-01

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5–5 mg kg−1, s.c.), an α7 nicotinic receptor antagonist, nor dihydro-β-erythroidine (0.5–2 mg kg−1, s.c.), an α4β2 nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01–0.2 mg kg−1, s.c.) dose-dependently reversed the disruption of PPI induced by apomorphine (1 mg kg−1, s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg−1, s.c.). The reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg−1) was eliminated by mecamylamine (1 mg kg−1, i.p.), but not by hexamethonium (10 mg kg−1, i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine-induced PPI disruption was dose-dependently blocked by methyllycaconitine (1 and 2 mg kg−1, s.c.). However, dihydro-β-erythroidine (1 and 2 mg kg−1, s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine-induced PPI through central α7 nicotinic receptors. PMID:15197106

Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents.

PubMed

Gacsályi, István; Nagy, Katalin; Pallagi, Katalin; Lévay, György; Hársing, László G; Móricz, Krisztina; Kertész, Szabolcs; Varga, Péter; Haller, József; Gigler, Gábor; Szénási, Gábor; Barkóczy, József; Bíró, Judit; Spedding, Michael; Antoni, Ferenc A

2013-01-01

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α(1), α(2c), 5-HT(2A) 5-HT₇, moderate affinity for adrenergic α(2a) and D₂ receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT₇ receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Copyright © 2012 Elsevier Ltd. All rights reserved.

GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice

PubMed Central

Rajagopal, Lakshmi; Burgdorf, Jeffrey S.; Moskal, Joseph R.; Meltzer, Herbert Y.

2016-01-01

GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-d-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg. i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications. PMID:26632337

Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action.

PubMed

Riordan, Alexander J; Schaler, Ari W; Fried, Jenny; Paine, Tracie A; Thornton, Janice E

2018-05-01

The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABA A agonist, GABA A antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABA A agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABA A receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them. Copyright © 2018 Elsevier Ltd. All rights reserved.

In vivo labeling of phencyclidine (PCP) receptors with sup 3 H-TCP in the mouse brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maurice, T.; Vignon, J.

1990-07-01

The phencyclidine (PCP) derivative N-(1-(2-thienyl)cyclohexyl)-piperidine (3H-TCP) was used to label in vivo the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel in the mouse brain. After the injection of a tracer dose of 3H-TCP, a spread labeling throughout the brain was observed, but was the highest in the cerebellum. Preadministration of unlabeled TCP (30 mg/kg) resulted in a 90% reduction of 3H-TCP binding. PCP, TCP, MK-801, dexoxadrol, ketamine, and SKF 10,047 isomers dose-dependently prevented the in vivo 3H-TCP binding. ID50 determined in the cerebrum and the cerebellum were respectively correlated with K0.5 for 3H TCP high (rat cortex) and low affinity (rat cerebellum)more » sites in vitro. The pharmacological specificity of the 3H-TCP binding site in the cerebellum was significantly different from that in the cerebrum. ID50 values were generally higher than in the cerebrum and, particularly, MK-801, the most potent drug in the cerebrum, was without significant effect in the cerebellum, at any time and at doses as high as 30 mg/kg. N-(1-(2-benzo(b) thiophenyl)cyclohexyl)piperidine (BTCP), desipramine, and atropine showed a more efficient prevention of 3H-TCP binding in the cerebellum than in the cerebrum. The prevention of the binding by TCP or PCP, at doses close to their ID50 values, was rapid and then decreased slowly. The effect of MK-801 was long-lasting. This study confirm previous in vitro studies: 3H-TCP is an efficient tool for the labeling of the NMDA receptor-associated ionic channel.« less

A multiple drug fatality involving MK-801 (dizocilpine), a mimic of phencyclidine.

PubMed

Mozayani, Ashraf; Schrode, Paul; Carter, Joye; Danielson, Terry J

2003-04-23

MK-801 (dizocilpine) is a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) family of glutamate receptors in the central nervous system. It is an anticonvulsant and also shares several pharmacological properties with phencyclidine and ketamine. It is not observed routinely as a substance of abuse. The deceased, a 45-year-old white male, obtained MK-801 surreptitiously in an attempt to treat a self-diagnosed depression. He was discovered the next morning, unresponsive on the bathroom floor. An empty bottle, labeled to contain 25mg of MK-801, was found near the body. The autopsy was performed at the Joseph A Jachimczyk Forensic Center, Houston, TX. Body weight at autopsy was 88kg. Lungs were edematous and congested (right: 775g; left 700g). The heart had proportionate chambers and was otherwise unremarkable. The kidneys (right: 220g; left 225g) were smooth surfaced. The brain (1550g) was congested and without trauma. Microscopic evaluation of the heart, kidneys and lungs showed normal histology and confirmed pulmonary congestion and edema. Samples of heart blood, liver, bile, vitreous humor, stomach contents and urine were collected at autopsy. There were 550ml of stomach contents. Drugs in blood were screened by EMIT II Plus immunoassay procedures and by gas chromatography/mass spectrometry (GC/MS) of an organic solvent extract of basified blood. Alcohol was determined by gas chromatography with headspace injection. MK-801, benzodiazepines and alcohol were detected in blood. Amounts of MK-801 present in blood, bile, liver, vitreous humor and urine were 0.15, 0.29, 0.92, less than 0.1 and 0.36 mg/l (kg), respectively. The cause of death was benzodiazepine, dizocilpine and ethanol toxicity and the manner accidental.

Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, alpha(1)- and 5-HT(2A)-receptors.

PubMed

Sebban, Claude; Tesolin-Decros, Brigitte; Ciprian-Ollivier, Jorge; Perret, Laurent; Spedding, Michael

2002-01-01

1. The electroencephalographic (EEG) effects of the propsychotic agent phencyclidine (PCP), were studied in conscious rats using power spectra (0 - 30 Hz), from the prefrontal cortex or sensorimotor cortex. PCP (0.1 - 3 mg kg(-1) s.c.) caused a marked dose-dependent increase in EEG power in the frontal cortex at 1 - 3 Hz with decreases in power at higher frequencies (9 - 30 Hz). At high doses (3 mg kg(-1) s.c.) the entire spectrum shifted to more positive values, indicating an increase in cortical synchronization. MK 801 (0.05 - 0.1 mg kg(-1) i.p.) caused similar effects but with lesser changes in power. 2. In contrast, the non-competitive AMPA antagonists GYKI 52466 and GYKI 53655 increased EEG power over the whole power spectrum (1 - 10 mg kg(-1) i.p.). The atypical antipsychotic clozapine (0.2 mg kg(-1) s.c.) synchronized the EEG (peak 8 Hz). The 5-HT(2A)-antagonist, M100907, specifically increased EEG power at 2 - 3 Hz at low doses (10 and 50 microg kg(-1) s.c.), whereas at higher doses (0.1 mg kg(-1) s.c.) the profile resembled that of clozapine. 3. Clozapine (0.2 mg kg(-1) s.c. ), GYKI 53655 (5 mg kg(-1) i.p.), prazosin (0.05 and 0.1 mg kg(-1) i.p.), and M100907 (0.01 and 0.05 mg kg(-1) s.c.) antagonized the decrease in power between 5 and 30 Hz caused by PCP (1 mg kg(-1) s.c.), but not the increase in power at 1 - 3 Hz in prefrontal cortex.

THE REELIN RECEPTORS VLDLR AND ApoER2 REGULATE SENSORIMOTOR GATING IN MICE

PubMed Central

Barr, Alasdair M.; Fish, Kenneth N.; Markou, Athina

2007-01-01

Summary Postmortem brain loss of reelin is noted in schizophrenia patients. Accordingly, heterozygous reeler mutant mice have been proposed as a putative model of this disorder. Little is known, however, about the involvement of the two receptors for reelin, Very-Low-Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2), on pre-cognitive processes of relevance to deficits seen in schizophrenia. Thus, we evaluated sensorimotor gating in mutant mice heterozygous or homozygous for the two reelin receptors. Mutant mice lacking one of these reelin receptors were tested for prepulse inhibition (PPI) of the acoustic startle reflex prior to and following puberty, and on a crossmodal PPI task, involving the presentation of acoustic and tactile stimuli. Furthermore, because schizophrenia patients show increased sensitivity to N-methyl-D-aspartate (NMDA) receptor blockade, we assessed the sensitivity of these mice to the PPI-disruptive effects of the NMDA receptor antagonist phencyclidine. The results demonstrated that acoustic PPI did not differ between mutant and wildtype mice. However, VLDLR homozygous mice displayed significant deficits in crossmodal PPI, while ApoER2 heterozygous and homozygous mice displayed significantly increased crossmodal PPI. Both ApoER2 and VLDLR heterozygous and homozygous mice exhibited greater sensitivity to the PPI-disruptive effects of phencyclidine than wildtype mice. These results indicate that partial or complete loss of either one of the reelin receptors results in a complex pattern of alterations in PPI function that include alterations in crossmodal, but not acoustic, PPI and increased sensitivity to NMDA receptor blockade. Thus, reelin receptor function appears to be critically involved in crossmodal PPI and the modulation of the PPI response by NMDA receptors. These findings have relevance to a range of neuropsychiatric disorders that involve sensorimotor gating deficits, including schizophrenia.. PMID:17261317

5 CFR 831.101 - Administration.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Administration. 831.101 Section 831.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.101 Administration. (a) OPM has charge of the...

5 CFR 831.101 - Administration.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Administration. 831.101 Section 831.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.101 Administration. (a) OPM has charge of the...

5 CFR 831.101 - Administration.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Administration. 831.101 Section 831.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.101 Administration. (a) OPM has charge of the...

5 CFR 831.101 - Administration.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Administration. 831.101 Section 831.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.101 Administration. (a) OPM has charge of the...

The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications

PubMed Central

Carty, N C; Xu, J; Kurup, P; Brouillette, J; Goebel-Goody, S M; Austin, D R; Yuan, P; Chen, G; Correa, P R; Haroutunian, V; Pittenger, C; Lombroso, P J

2012-01-01

Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP61 is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP61 levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP61 after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP61. STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP61 levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP61 and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP61 accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP61 inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ. PMID:22781170

Behavioural pharmacology of the α5-GABAA receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models.

PubMed

Gacsályi, István; Móricz, Krisztina; Gigler, Gábor; Wellmann, János; Nagy, Katalin; Ling, István; Barkóczy, József; Haller, József; Lambert, Jeremy J; Szénási, Gábor; Spedding, Michael; Antoni, Ferenc A

2017-10-01

Previous work has shown that S44819 is a novel GABAA receptor (GABA A R) antagonist, which is selective for extrasynaptic GABA A Rs incorporating the α5 subunit (α5-GABA A Rs). The present study reports on the preclinical neuropsychopharmacological profile of S44819. Significantly, no sedative or pro-convulsive side effects of S44819 were found at doses up to 30 mg/kg i.p. Object recognition (OR) memory in intact mice was enhanced by S44819 (0.3 mg/kg p.o.) given before the acquisition trial. Mice treated with phencyclidine for two weeks and tested six days after the cessation of treatment failed to show OR memory. This deficit was corrected by a single administration of S44819 (0.1, 0.3 or 1 mg/kg p.o.) prior to the acquisition trial. The amnestic effect of ketamine in rats tested in the eight-arm radial maze (reference and working memory versions) was blocked by S44819 (3 mg/kg p.o.). Extinction of cued fear was preserved during treatment with S44819 (3 mg/kg/diem i.p.). Administration of S44819 had no significant effect in the Vogel-conflict test, the elevated plus maze, the forced swim, the marble-burying and the tail-suspension tests. In contrast, anxiolytic/antidepressant-like effects of the compound were found in paradigms that have mnemonic components, such as social interaction, fear-potentiated startle and social avoidance induced by negative life experience. In summary, S44819 enhanced intact recognition memory and ameliorated memory deficits induced by inhibition of NMDA receptors. Anxiolytic/antidepressant efficacy was limited to paradigms involving cognitive function. In conclusion, S44819 is a novel psychoactive pro-cognitive compound with potential as a therapeutic agent in dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

5 CFR 831.1212 - Administrative review of OPM decisions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Administrative review of OPM decisions. 831.1212 Section 831.1212 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1212 Administrative review of OPM...

5 CFR 831.1212 - Administrative review of OPM decisions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Administrative review of OPM decisions. 831.1212 Section 831.1212 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1212 Administrative review of OPM...

5 CFR 930.205 - Administrative law judge pay system.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Administrative law judge pay system. 930.205 Section 930.205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law...

5 CFR 930.205 - Administrative law judge pay system.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Administrative law judge pay system. 930.205 Section 930.205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law...

5 CFR 930.205 - Administrative law judge pay system.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Administrative law judge pay system. 930.205 Section 930.205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law...

5 CFR 930.205 - Administrative law judge pay system.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Administrative law judge pay system. 930.205 Section 930.205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law...

5 CFR 930.205 - Administrative law judge pay system.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Administrative law judge pay system. 930.205 Section 930.205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law...

7 CFR 201.3 - Administrator.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Administration § 201.3 Administrator. The Administrator of the Agricultural Marketing Service may...

7 CFR 201.3 - Administrator.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Administration § 201.3 Administrator. The Administrator of the Agricultural Marketing Service may...

47 CFR 52.13 - North American Numbering Plan Administrator.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 3 2010-10-01 2010-10-01 false North American Numbering Plan Administrator. 52.13 Section 52.13 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) NUMBERING Administration § 52.13 North American Numbering Plan Administrator. (a) The North American Numbering Plan Administrator ...

Rhabdomyolysis After LSD Ingestion.

PubMed

Berrens, Zachary; Lammers, Jessica; White, Christopher

2010-01-01

Rhabdomyolysis involves the release of intracellular contents secondary to muscle cell injury; it generally presents with muscle pain and weakness. Illicit drugs, including phencyclidine, MDMA ("ecstasy"), and cocaine, are frequently documented as a cause of rhabdomyolysis. The authors review the literature on LSD-associated rhabdomyolysis. The authors provide a new case report of a previously health patient who suffered rhabdomyolysis after LSD ingestion. Although frequently listed as a cause of rhabdomyolysis, there are only limited reports of rhabdomyolysis in patients who have ingested LSD. The discussion outlines potential mechanisms and management of LSD-associated rhabdomyolysis. Consultation psychiatrists may be called to assist in management of acute mental-status changes or agitation associated with LSD intoxication in addition to facilitating subsequent chemical-dependency treatment.

5 CFR 930.208 - Administrative Law Judge Loan Program-detail to other agencies.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Administrative Law Judge Loan Program... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.208 Administrative Law Judge Loan Program—detail to other...

5 CFR 930.208 - Administrative Law Judge Loan Program-detail to other agencies.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Administrative Law Judge Loan Program... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.208 Administrative Law Judge Loan Program—detail to other...

5 CFR 930.208 - Administrative Law Judge Loan Program-detail to other agencies.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Administrative Law Judge Loan Program... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.208 Administrative Law Judge Loan Program—detail to other...

5 CFR 930.208 - Administrative Law Judge Loan Program-detail to other agencies.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Administrative Law Judge Loan Program... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.208 Administrative Law Judge Loan Program—detail to other...

5 CFR 930.208 - Administrative Law Judge Loan Program-detail to other agencies.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Administrative Law Judge Loan Program... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.208 Administrative Law Judge Loan Program—detail to other...

Perceived Value of University-Based Continuing Education Leadership Development Programs for Administrators

ERIC Educational Resources Information Center

Stone, Geri L.; Major, Claire H.

2014-01-01

This quantitative study, which involved development of a Value Creation Survey, examined the perceived value of leadership development programs (LDPs) provided by continuing higher education for administrators in colleges and universities. Participants were administrators at Association for Continuing Higher Education (ACHE) member institutions.…

Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

PubMed Central

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-01-01

Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

Dispersive liquid-liquid microextraction prior to field-amplified sample injection for the sensitive analysis of 3,4-methylenedioxymethamphetamine, phencyclidine and lysergic acid diethylamide by capillary electrophoresis in human urine.

PubMed

Airado-Rodríguez, Diego; Cruces-Blanco, Carmen; García-Campaña, Ana M

2012-12-07

A novel capillary zone electrophoresis (CZE) with ultraviolet detection method has been developed and validated for the analysis of 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD) and phencyclidine (PCP) in human urine. The separation of these three analytes has been achieved in less than 8 min in a 72-cm effective length capillary with 50-μm internal diameter. 100 mM NaH(2)PO(4)/Na(2)HPO(4), pH 6.0 has been employed as running buffer, and the separation has been carried out at temperature and voltage of 20°C, and 25kV, respectively. The three drugs have been detected at 205 nm. Field amplified sample injection (FASI) has been employed for on-line sample preconcentration. FASI basically consists in a mismatch between the electric conductivity of the sample and that of the running buffer and it is achieved by electrokinetically injecting the sample diluted in a solvent of lower conductivity than that of the carrier electrolyte. Ultrapure water resulted to be the better sample solvent to reach the greatest enhancement factor. Injection voltage and time have been optimized to 5 kV and 20s, respectively. The irreproducibility associated to electrokinetic injection has been correcting by using tetracaine as internal standard. Dispersive liquid-liquid microextraction (DLLME) has been employed as sample treatment using experimental design and response surface methodology for the optimization of critical variables. Linear responses were found for MDMA, PCP and LSD in presence of urine matrix between 10.0 and 100 ng/mL approximately, and LODs of 1.00, 4.50, and 4.40 ng/mL were calculated for MDMA, PCP and LSD, respectively. The method has been successfully applied to the analysis of the three drugs of interest in human urine with satisfactory recovery percentages. Copyright © 2012 Elsevier B.V. All rights reserved.

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.

PubMed

Engel, Martin; Snikeris, Peta; Matosin, Natalie; Newell, Kelly Anne; Huang, Xu-Feng; Frank, Elisabeth

2016-04-01

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT1A Receptor-Dependent Mechanism

PubMed Central

Kargieman, Lucila; Riga, Maurizio S; Artigas, Francesc; Celada, Pau

2012-01-01

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)—used as a pharmacological model of schizophrenia—disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15–4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT2A and 5-HT1A receptors (5-HT2AR and 5-HT1AR, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT2AR and behaves as partial agonist in vivo at 5-HT1AR. We used wild-type (WT) mice and 5-HT1AR and 5-HT2AR knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n=23, 13, 11, respectively; p<0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT1AR antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT1AR activation without the need to block 5-HT2AR, as observed with clozapine-induced cortical dopamine release. PMID:22012474

Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies.

PubMed

Andrews, Jessica L; Goodfellow, Frederic J; Matosin, Natalie; Snelling, Mollie K; Newell, Kelly A; Huang, Xu-Feng; Fernandez-Enright, Francesca

2017-07-01

Gene expression analyses in post-mortem schizophrenia brains suggest that a number of ubiquitin proteasome system (UPS) genes are associated with schizophrenia; however the status of UPS proteins in the schizophrenia brain is largely unknown. Ubiquitin related proteins are inherently involved in memory, neuronal survival and morphology, which are processes implicated in neurodevelopmental disorders such as schizophrenia. We examined levels of five UPS proteins (Protein Inhibitor of Activated STAT2 [PIAS2], F-Box and Leucine rich repeat protein 21 [FBXL21], Mouse Double Minute 2 homolog [MDM2], Ubiquitin Carboxyl-Terminal Hydrolase-L1 [UCHL1] and Ubiquitin Conjugating Enzyme E2D1 [UBE2D1]) involved in these neuronal processes, within the dorsolateral prefrontal cortex of post-mortem schizophrenia subjects and matched controls (n = 30/group), in addition to across neurodevelopmental time-points (juvenile, adolescent and adult stages of life), utilizing a well-established neurodevelopmental phencyclidine (PCP) animal model of schizophrenia. We observed significant reductions in PIAS2, FBXL21 and MDM2 in schizophrenia subjects compared to controls (p-values ranging from 0.002 to 0.004). In our developmental PCP model, MDM2 protein was significantly reduced in adult PCP-treated rats compared to controls (p = 0.034). Additionally, FBXL21 (p = 0.022) and UCHL1 (p = 0.022) were significantly decreased, whilst UBE2D1 was increased (p = 0.022), in juvenile phencyclidine-treated rats compared to controls. This is the first study reporting alterations of UPS proteins in post-mortem human schizophrenia subjects and in a neurodevelopmental model of schizophrenia. The findings from this study provide strong support for a role of these UPS proteins in the pathology and development of schizophrenia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor

PubMed Central

Hamouda, Ayman K.; Wang, Ze-Jun; Stewart, Deirdre S.; Jain, Atul D.; Glennon, Richard A.

2015-01-01

Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) of α4β2 and α2β2 nAChRs that, at concentrations >1 µM, also inhibits these receptors and α7 nAChRs. However, its interactions with muscle-type nAChRs have not been characterized, and the locations of its binding site(s) in any nAChR are not known. We report here that dFBr inhibits human muscle (αβεδ) and Torpedo (αβγδ) nAChR expressed in Xenopus oocytes with IC50 values of ∼1 μM. dFBr also inhibited the equilibrium binding of ion channel blockers to Torpedo nAChRs with higher affinity in the nAChR desensitized state ([3H]phencyclidine; IC50 = 4 μM) than in the resting state ([3H]tetracaine; IC50 = 60 μM), whereas it bound with only very low affinity to the ACh binding sites ([3H]ACh, IC50 = 1 mM). Upon irradiation at 312 nm, [3H]dFBr photoincorporated into amino acids within the Torpedo nAChR ion channel with the efficiency of photoincorporation enhanced in the presence of agonist and the agonist-enhanced photolabeling inhibitable by phencyclidine. In the presence of agonist, [3H]dFBr also photolabeled amino acids in the nAChR extracellular domain within binding pockets identified previously for the nonselective nAChR PAMs galantamine and physostigmine at the canonical α-γ interface containing the transmitter binding sites and at the noncanonical δ-β subunit interface. These results establish that dFBr inhibits muscle-type nAChR by binding in the ion channel and that [3H]dFBr is a photoaffinity probe with broad amino acid side chain reactivity. PMID:25870334

A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia.

PubMed

Gil-Ad, Irit; Portnoy, Moshe; Tarasenko, Igor; Bidder, Miri; Kramer, Maria; Taler, Michal; Weizman, Abraham

2014-03-01

Schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl-D-aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25-50mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5mg/kg ip) hyperactivity. PGW5 (25mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis. PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

PubMed

Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

2007-06-01

Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

Neural basis of the potentiated inhibition of repeated haloperidol and clozapine treatment on the phencyclidine-induced hyperlocomotion

PubMed Central

Zhao, Changjiu; Sun, Tao; Li, Ming

2012-01-01

Clinical observations suggest that antipsychotic effect starts early and increases progressively over time. This time course of antipsychotic effect can be captured in a rat phencyclidine (PCP)-induced hyperlocomotion model, as repeated antipsychotic treatment progressively increases its inhibition of the repeated PCP-induced hyperlocomotion. Although the neural basis of acute antipsychotic action has been studied extensively, the system that mediates the potentiated effect of repeated antipsychotic treatment has not been elucidated. In the present study, we investigated the neuroanatomical basis of the potentiated action of haloperidol (HAL) and clozapine (CLZ) treatment in the repeated PCP-induced hyperlocomotion. Once daily for five consecutive days, adult Sprague-Dawley male rats were first injected with HAL (0.05 mg/kg, sc), CLZ (10.0 mg/kg, sc) or saline, followed by an injection of PCP (3.2 mg/kg, sc) or saline 30 min later, and motor activity was measured for 90 min after the PCP injection. C-Fos immunoreactivity was assessed either after the acute (day 1) or repeated (day 5) drug tests. Behaviorally, repeated HAL or CLZ treatment progressively increased the inhibition of PCP-induced hyperlocomotion throughout the five days of drug testing. Neuroanatomically, both acute and repeated treatment of HAL significantly increased PCP-induced c-Fos expression in the nucleus accumbens shell (NAs) and the ventral tegmental area (VTA), but reduced it in the central amygdaloid nucleus (CeA). Acute and repeated CLZ treatment significantly increased PCP-induced c-Fos expression in the ventral part of lateral septal nucleus (LSv) and VTA, but reduced it in the medial prefrontal cortex (mPFC). More importantly, the effects of HAL and CLZ in these brain areas underwent a time-dependent reduction from day 1 to day 5. These findings suggest that repeated HAL achieves its potentiated inhibition of the PCP-induced hyperlocomotion by acting on the NAs, CeA and VTA, while CLZ does so by acting on the mPFC, LSv and VTA. PMID:22476004

1-cyclohexyl-x-methoxybenzene derivatives, novel psychoactive substances seized on the internet market. Synthesis and in vivo pharmacological studies in mice.

PubMed

Fantinati, Anna; Ossato, Andrea; Bianco, Sara; Canazza, Isabella; De Giorgio, Fabio; Trapella, Claudio; Marti, Matteo

2017-05-01

Among novel psychoactive substances notified to EMCDDA and Europol were 1-cyclohexyl-x-methoxybenzene stereoisomers (ortho, meta, and para). These substances share some structural characteristics with phencyclidine and tramadol. Nowadays, no information on the pharmacological and toxicological effects evoked by 1-cyclohexyl-x-methoxybenzene are reported. The aim of this study was to investigate the effect evoked by each one stereoisomer on visual stimulation, body temperature, acute thermal pain, and motor activity in mice. Mice were evaluated in behavioral tests carried out in a consecutive manner according to the following time scheme: observation of visual placing response, measures of core body temperature, determination of acute thermal pain, and stimulated motor activity. All three stereoisomers dose-dependent inhibit visual placing response (rank order: meta > ortho > para), induce hyperthermia at lower and hypothermia at higher doses (meta > ortho > para) and cause analgesia to thermal stimuli (para > meta = ortho), while they do not alter motor activity. For the first time, this study demonstrates that systemic administration of 1-cyclohexyl-x-methoxybenzene compounds markedly inhibit visual response, promote analgesia, and induce core temperature alterations in mice. This data, although obtained in animal model, suggest their possible hazard for human health (i.e., hyperthermia and sensorimotor alterations). In particular, these novel psychoactive substances may have a negative impact in many daily activities, greatly increasing the risk factors for workplace accidents and traffic injuries. Copyright © 2017 John Wiley & Sons, Ltd.

Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

PubMed

Seillier, Alexandre; Giuffrida, Andrea

2016-02-01

Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

PubMed Central

Javitt, Daniel C.

2012-01-01

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia. PMID:22987851

49 CFR 193.2007 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY LIQUEFIED NATURAL GAS FACILITIES... Administrator, Pipeline and Hazardous Materials Safety Administration or his or her delegate. Ambient vaporizer...

42 CFR 431.713 - Continuing study and investigation.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Programs for Licensing Nursing Home Administrators § 431.713 Continuing study and investigation. The agency or board must conduct a continuing study of nursing homes and administrators within the State to...

32 CFR 635.4 - Administration of expelled or barred persons file.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Administration of expelled or barred persons file. 635.4 Section 635.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL INVESTIGATIONS LAW ENFORCEMENT REPORTING Records Administration § 635.4 Administration of expelled or barred...

5 CFR 831.203 - Continuation of coverage for employees of the Metropolitan Washington Airports Authority.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Continuation of coverage for employees of the Metropolitan Washington Airports Authority. 831.203 Section 831.203 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Coverage...

5 CFR 831.203 - Continuation of coverage for employees of the Metropolitan Washington Airports Authority.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Continuation of coverage for employees of the Metropolitan Washington Airports Authority. 831.203 Section 831.203 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Coverage...

5 CFR 930.202 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in civil service or pay status. Removal means discharge of an administrative law judge from the... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.202...

5 CFR 930.210 - Reduction in force.

Code of Federal Regulations, 2011 CFR

2011-01-01

....210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program..., the reduction in force regulations in part 351 of this chapter apply to administrative law judges. (b...

5 CFR 930.203 - Cost of competitive examination.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section 930.203 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.203 Cost of competitive examination. Each agency employing administrative law judges...

5 CFR 930.203 - Cost of competitive examination.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Section 930.203 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.203 Cost of competitive examination. Each agency employing administrative law judges...

5 CFR 930.202 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... in civil service or pay status. Removal means discharge of an administrative law judge from the... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.202...

5 CFR 930.210 - Reduction in force.

Code of Federal Regulations, 2013 CFR

2013-01-01

....210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program..., the reduction in force regulations in part 351 of this chapter apply to administrative law judges. (b...

5 CFR 930.202 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... in civil service or pay status. Removal means discharge of an administrative law judge from the... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.202...

5 CFR 930.203 - Cost of competitive examination.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Section 930.203 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.203 Cost of competitive examination. Each agency employing administrative law judges...

5 CFR 930.202 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... in civil service or pay status. Removal means discharge of an administrative law judge from the... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.202...

5 CFR 930.210 - Reduction in force.

Code of Federal Regulations, 2012 CFR

2012-01-01

....210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program..., the reduction in force regulations in part 351 of this chapter apply to administrative law judges. (b...

5 CFR 930.202 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... in civil service or pay status. Removal means discharge of an administrative law judge from the... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.202...

Absence of histological changes after the administration of a continuous intrathecal clonidine in Wistar rats.

PubMed

Guevara-López, Uriah; Aldrete, J Antonio; Covarrubias-Gómez, Alfredo; Hernández-Pando, Rogelio E; López-Muñoz, Francisco J

2009-01-01

The administration of epidural and spinal clonidine has demonstrated an antinociceptive effect in animals and humans. For that reason, its spinal administration has been proposed as an adjuvant in chronic pain management. However, there is limited information about its possible neurotoxic effect after its continuous neuraxial administration. Twelve male Wistar rats were randomly divided into two groups. Using an osmotic mini-pump a continuous infusion of intrathecal clonidine, (21.4 micrograms/day, Group A) or saline solution (Group B), was administered for 14 consecutive days. For evaluating the neurological damage a neuropathological analysis of the spinal cord was performed by light microscopy. Neurohistopathologic examination of the spinal cord specimens failed to show evidence of neurotoxic damage in either group. These findings showed that continuous intrathecal administration of clonidine did not produce evidence of histological neurotoxicity; therefore it is possible that continuous administration of intrathecal clonidine might be a safe option for treatment of chronic intractable pain; however, further investigations are necessary for evaluating diverse doses and periods of time, and to define its possible behavioral effects.

42 CFR 431.713 - Continuing study and investigation.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 4 2011-10-01 2011-10-01 false Continuing study and investigation. 431.713 Section... Programs for Licensing Nursing Home Administrators § 431.713 Continuing study and investigation. The agency or board must conduct a continuing study of nursing homes and administrators within the State to...

42 CFR 431.713 - Continuing study and investigation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Continuing study and investigation. 431.713 Section... Programs for Licensing Nursing Home Administrators § 431.713 Continuing study and investigation. The agency or board must conduct a continuing study of nursing homes and administrators within the State to...

5 CFR 831.206 - Continuation of coverage for former Federal employees of the Civilian Marksmanship Program.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Continuation of coverage for former Federal employees of the Civilian Marksmanship Program. 831.206 Section 831.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Coverage...

5 CFR 890.1032 - Length of suspension.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Length of suspension. 890.1032 Section 890.1032 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care...

5 CFR 891.105 - Correction of errors.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Correction of errors. 891.105 Section 891.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIRED FEDERAL EMPLOYEES HEALTH BENEFITS Administration and General Provisions § 891.105...

5 CFR 890.1033 - Notice of suspension.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Notice of suspension. 890.1033 Section 890.1033 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care...

5 CFR 930.206 - Performance rating and awards.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Section 930.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law... an administrative law judge. (b) An agency may not grant any monetary or honorary award or incentive...

5 CFR 930.201 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.201... be conducted in accordance with 5 U.S.C. 556 and 557 and to administrative law judge positions. (b...

5 CFR 930.206 - Performance rating and awards.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Section 930.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law... an administrative law judge. (b) An agency may not grant any monetary or honorary award or incentive...

5 CFR 930.201 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.201... be conducted in accordance with 5 U.S.C. 556 and 557 and to administrative law judge positions. (b...

5 CFR 930.201 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.201... be conducted in accordance with 5 U.S.C. 556 and 557 and to administrative law judge positions. (b...

5 CFR 930.206 - Performance rating and awards.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Section 930.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law... an administrative law judge. (b) An agency may not grant any monetary or honorary award or incentive...

5 CFR 930.206 - Performance rating and awards.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section 930.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law... an administrative law judge. (b) An agency may not grant any monetary or honorary award or incentive...

5 CFR 930.206 - Performance rating and awards.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Section 930.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law... an administrative law judge. (b) An agency may not grant any monetary or honorary award or incentive...

Increased 1-year continuation of DMPA among women randomized to self-administration: results from a randomized controlled trial at Planned Parenthood.

PubMed

Kohn, Julia E; Simons, Hannah R; Della Badia, Lisa; Draper, Elissa; Morfesis, Johanna; Talmont, Elizabeth; Beasley, Anitra; McDonald, Melanie; Westhoff, Carolyn L

2018-03-01

Self-administration of subcutaneous depot medroxyprogesterone acetate (DMPA-sc) is feasible, acceptable, and effective. Our objective was to compare one-year continuation of DMPA-sc between women randomized to self-administration versus clinic administration. We randomized 401 females ages 15-44 requesting DMPA at clinics in Texas and New Jersey to self-administration or clinic administration in a 1:1 allocation. Clinic staff taught participants randomized to self-administration to self-inject and observed the first injection; participants received instructions, a sharps container, and three doses for home use. Participants randomized to clinic administration received usual care. All participants received DMPA-sc at no cost and injection reminders via text message or email. We conducted follow-up surveys at six and 12 months. Three hundred thirty-six participants (84%) completed the 12-month survey; 316 completed both follow-up surveys (an 80% response rate excluding eight withdrawals). Participants ranged in age from 16-44. One-year DMPA continuous use was 69% in the self-administration group and 54% in the clinic group (p=.005). There were three self-reported pregnancies during the study period, all occurred in the clinic group; all three women had discontinued DMPA and one reported her pregnancy as intended. Among the self-administration group, 97% reported that self-administration was very or somewhat easy; 87% would recommend self-administration of DMPA-sc to a friend. Among the clinic group, 52% reported interest in self-administration in the future. Satisfaction was similar between groups. No serious adverse events were reported. DMPA self-administration improves contraceptive continuation and is a feasible and acceptable option for women and adolescents. Self-administration of subcutaneous DMPA can improve contraceptive access, autonomy, and continuation, and is a feasible and acceptable option for women and adolescents. It should be made widely available as an option for women and adolescents. Copyright © 2017 Elsevier Inc. All rights reserved.

5 CFR 831.113 - Payments to children.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Payments to children. 831.113 Section 831.113 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.113 Payments to children. For purposes of...

5 CFR 831.113 - Payments to children.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Payments to children. 831.113 Section 831.113 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.113 Payments to children. For purposes of...

5 CFR 831.113 - Payments to children.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Payments to children. 831.113 Section 831.113 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.113 Payments to children. For purposes of...

5 CFR 831.113 - Payments to children.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Payments to children. 831.113 Section 831.113 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.113 Payments to children. For purposes of...

5 CFR 831.113 - Payments to children.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Payments to children. 831.113 Section 831.113 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.113 Payments to children. For purposes of...

40 CFR 72.12 - Administrative appeals.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Administrative appeals. 72.12 Section 72.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Program General Provisions § 72.12 Administrative appeals. The procedures for...

40 CFR 72.12 - Administrative appeals.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 17 2012-07-01 2012-07-01 false Administrative appeals. 72.12 Section 72.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Program General Provisions § 72.12 Administrative appeals. The procedures for...

40 CFR 72.12 - Administrative appeals.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 17 2014-07-01 2014-07-01 false Administrative appeals. 72.12 Section 72.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Program General Provisions § 72.12 Administrative appeals. The procedures for...

40 CFR 72.12 - Administrative appeals.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 16 2011-07-01 2011-07-01 false Administrative appeals. 72.12 Section 72.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Program General Provisions § 72.12 Administrative appeals. The procedures for...

40 CFR 72.12 - Administrative appeals.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Administrative appeals. 72.12 Section 72.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Program General Provisions § 72.12 Administrative appeals. The procedures for...

7 CFR 1776.13 - Administrative expenses.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 12 2014-01-01 2013-01-01 true Administrative expenses. 1776.13 Section 1776.13 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) HOUSEHOLD WATER WELL SYSTEM GRANT PROGRAM HWWS Grants § 1776.13 Administrative...

7 CFR 1776.13 - Administrative expenses.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 12 2013-01-01 2013-01-01 false Administrative expenses. 1776.13 Section 1776.13 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) HOUSEHOLD WATER WELL SYSTEM GRANT PROGRAM HWWS Grants § 1776.13 Administrative...

7 CFR 1776.13 - Administrative expenses.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 12 2010-01-01 2010-01-01 false Administrative expenses. 1776.13 Section 1776.13 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) HOUSEHOLD WATER WELL SYSTEM GRANT PROGRAM HWWS Grants § 1776.13 Administrative...

7 CFR 1776.13 - Administrative expenses.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 12 2012-01-01 2012-01-01 false Administrative expenses. 1776.13 Section 1776.13 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) HOUSEHOLD WATER WELL SYSTEM GRANT PROGRAM HWWS Grants § 1776.13 Administrative...

7 CFR 1776.13 - Administrative expenses.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 12 2011-01-01 2011-01-01 false Administrative expenses. 1776.13 Section 1776.13 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) HOUSEHOLD WATER WELL SYSTEM GRANT PROGRAM HWWS Grants § 1776.13 Administrative...

5 CFR 890.1101 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Purpose. 890.1101 Section 890.1101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Temporary Continuation of Coverage § 890.1101 Purpose. This subpart...

32 CFR 310.45 - Administrative remedies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 2 2011-07-01 2011-07-01 false Administrative remedies. 310.45 Section 310.45 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Privacy Act Violations § 310.45 Administrative remedies. Any individual who...

5 CFR 894.104 - Who makes enrollment decisions and reconsiderations?

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Who makes enrollment decisions and reconsiderations? 894.104 Section 894.104 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and...

32 CFR 631.10 - Administration.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Administration. 631.10 Section 631.10 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL... Disciplinary Control Boards § 631.10 Administration. (a) Commanders are authorized to acquire, report, process...

5 CFR 894.104 - Who makes enrollment decisions and reconsiderations?

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Who makes enrollment decisions and reconsiderations? 894.104 Section 894.104 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and...

5 CFR 894.104 - Who makes enrollment decisions and reconsiderations?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Who makes enrollment decisions and reconsiderations? 894.104 Section 894.104 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and...

40 CFR 57.814 - Administrative record.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Administrative record. 57.814 Section 57.814 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED... Technology § 57.814 Administrative record. (a) Establishment of record. (1) Upon receipt of request for a...

12 CFR 238.3 - Administration.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Administration. 238.3 Section 238.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) SAVINGS AND LOAN HOLDING COMPANIES (REGULATION LL) General Provisions § 238.3 Administration. (a...

32 CFR 631.10 - Administration.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 4 2012-07-01 2011-07-01 true Administration. 631.10 Section 631.10 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL... Disciplinary Control Boards § 631.10 Administration. (a) Commanders are authorized to acquire, report, process...

32 CFR 631.10 - Administration.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 4 2013-07-01 2013-07-01 false Administration. 631.10 Section 631.10 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL... Disciplinary Control Boards § 631.10 Administration. (a) Commanders are authorized to acquire, report, process...

12 CFR 238.3 - Administration.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Administration. 238.3 Section 238.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) SAVINGS AND LOAN HOLDING COMPANIES (REGULATION LL) General Provisions § 238.3 Administration. (a...

32 CFR 631.10 - Administration.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 4 2011-07-01 2011-07-01 false Administration. 631.10 Section 631.10 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL... Disciplinary Control Boards § 631.10 Administration. (a) Commanders are authorized to acquire, report, process...

5 CFR 960.103 - Location.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Location. 960.103 Section 960.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EXECUTIVE BOARDS § 960.103 Location. Federal Executive Boards have been established and shall continue in...

40 CFR 77.4 - Administrator's action on proposed offset plans.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Administrator's action on proposed offset plans. 77.4 Section 77.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) EXCESS EMISSIONS § 77.4 Administrator's action on proposed offset plans. (a...

12 CFR 225.3 - Administration.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 3 2013-01-01 2013-01-01 false Administration. 225.3 Section 225.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED... Administration. (a) Delegation of authority. Designated Board members and officers and the Federal Reserve Banks...

Effective method of continuous rocuronium administration based on effect-site concentrations using a pharmacokinetic/pharmacodynamic model during propofol-remifentanil anesthesia.

PubMed

Moriyama, Takahiro; Matsunaga, Akira; Nagata, Osamu; Enohata, Kei; Kamikawaji, Tomomi; Uchino, Erika; Kanmura, Yuichi

2015-08-01

Rocuronium bromide (Rb) is a rapid onset, intermediate-acting neuromuscular blocking agent that is suitable for continuous administration. The appropriate rate of rocuronium administration is, however, difficult to determine due to large interindividual differences in sensitivity to rocuronium. The aim of this study was to clarify whether the simulated rocuronium concentration at the time of recovery to %T1 > 0 % after the initial administration of rocuronium is a good indicator of optimal effect-site concentrations during continuous rocuronium administration. Twenty-one patients were anesthetized with propofol. After induction, Rb 0.6 mg/kg was administered intravenously, and nerve stimulation using the single stimulation mode was conducted every 15 s. When %T1 recovered to >0 % after the initial administration of Rb, the effect-site concentration of rocuronium, calculated by pharmacokinetic simulation with Wierda's set of parameters, was recorded and defined as the recovery concentration (Rb r.c.). The administration rate of rocuronium was adjusted to maintain the Rb r.c. during surgery. Rb administration was discontinued just before the end of surgery, and the recovery time until %T1 > 25 % was recorded. Plasma Rb concentrations were measured at 1 and 3 h after the initiation of continuous Rb administration. The mean Rb r.c. was 1.56 ± 0.35 μg/ml, with minimum and maximum values of 1.09 and 2.08 μg/ml, respectively. The %T1 did not increase above 10 % in any of the patients during continuous administration of Rb, and the recovery period to %T1 > 25 % ranged from 9 to 29 min. The effect-site concentrations of Rb calculated with Wierda's parameters significantly correlated with plasma concentrations (P < 0.01) at both 1 and 3 h after the initial administration of Rb. The results suggest that our method may be one of the most reliable protocols for the continuous administration of Rb described to date for maintaining suitable muscle relaxation during surgery without excessively prolonged effects.

49 CFR 224.5 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF... the Administrator of the Federal Railroad Administration or the Administrator's delegate. Associate Administrator means the Associate Administrator for Safety, Federal Railroad Administration, or the Associate...

5 CFR 894.105 - Who may correct an error in my enrollment?

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Who may correct an error in my enrollment? 894.105 Section 894.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and...

5 CFR 894.103 - How do I enroll?

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false How do I enroll? 894.103 Section 894.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and General Provisions § 894.103 How do I...

47 CFR 54.725 - Universal service disbursements during pendency of a request for review and Administrator decision.

Code of Federal Regulations, 2010 CFR

2010-10-01

... COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Review of Decisions... health care support mechanism, the Administrator shall not reimburse a service provider for the provision... Federal Communications Commission; provided, however, that the Administrator may disburse funds for any...

40 CFR 78.3 - Petition for administrative review and request for evidentiary hearing.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Petition for administrative review and request for evidentiary hearing. 78.3 Section 78.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPEAL PROCEDURES § 78.3 Petition for administrative review...

40 CFR 78.6 - Action on petition for administrative review.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Action on petition for administrative review. 78.6 Section 78.6 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPEAL PROCEDURES § 78.6 Action on petition for administrative review. (a) If no...

5 CFR 894.105 - Who may correct an error in my enrollment?

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Who may correct an error in my enrollment? 894.105 Section 894.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and...

5 CFR 894.103 - How do I enroll?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false How do I enroll? 894.103 Section 894.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and General Provisions § 894.103 How do I...

5 CFR 894.103 - How do I enroll?

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false How do I enroll? 894.103 Section 894.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and General Provisions § 894.103 How do I...

5 CFR 894.105 - Who may correct an error in my enrollment?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Who may correct an error in my enrollment? 894.105 Section 894.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES DENTAL AND VISION INSURANCE PROGRAM Administration and...

5 CFR 930.207 - Details and assignments to other duties within the same agency.

Code of Federal Regulations, 2010 CFR

2010-01-01

... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.207 Details and assignments to other duties within the same agency. (a) An agency may detail an administrative law judge from one administrative law judge...

5 CFR 930.207 - Details and assignments to other duties within the same agency.

Code of Federal Regulations, 2011 CFR

2011-01-01

... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.207 Details and assignments to other duties within the same agency. (a) An agency may detail an administrative law judge from one administrative law judge...

5 CFR 930.207 - Details and assignments to other duties within the same agency.

Code of Federal Regulations, 2013 CFR

2013-01-01

... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.207 Details and assignments to other duties within the same agency. (a) An agency may detail an administrative law judge from one administrative law judge...

5 CFR 930.207 - Details and assignments to other duties within the same agency.

Code of Federal Regulations, 2012 CFR

2012-01-01

... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.207 Details and assignments to other duties within the same agency. (a) An agency may detail an administrative law judge from one administrative law judge...

5 CFR 930.207 - Details and assignments to other duties within the same agency.

Code of Federal Regulations, 2014 CFR

2014-01-01

... (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Administrative Law Judge Program § 930.207 Details and assignments to other duties within the same agency. (a) An agency may detail an administrative law judge from one administrative law judge...

32 CFR 383a.8 - Administration.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 2 2012-07-01 2012-07-01 false Administration. 383a.8 Section 383a.8 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.8 Administration. (a) The Director and Deputy Director(s...

32 CFR 383a.8 - Administration.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 2 2014-07-01 2014-07-01 false Administration. 383a.8 Section 383a.8 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.8 Administration. (a) The Director and Deputy Director(s...

28 CFR 71.40 - Stays ordered by the Department of Justice.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Stays ordered by the Department of Justice. 71.40 Section 71.40 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) IMPLEMENTATION OF... finding that continuation of the administrative process described in this part with respect to a claim or...

75 FR 23582 - Federal Housing Administration: Continuation of FHA Reform-Strengthening Risk Management Through...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-04

...-AI81 Federal Housing Administration: Continuation of FHA Reform-- Strengthening Risk Management Through... Federal Housing Administration (FHA) that are designed to strengthen FHA by improving its management of risk. Although the preamble to the final rule correctly provides that the revised net worth...

Novel psychoactive substances of interest for psychiatry

PubMed Central

Schifano, Fabrizio; Orsolini, Laura; Duccio Papanti, G; Corkery, John M

2015-01-01

Novel psychoactive substances include synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, phencyclidine-like dissociatives, piperazines, GABA-A/B receptor agonists, a range of prescribed medications, psychoactive plants/herbs, and a large series of performance and image enhancing drugs. Users are typically attracted by these substances due to their intense psychoactive effects and likely lack of detection in routine drug screenings. This paper aims at providing psychiatrists with updated knowledge of the clinical pharmacology and psychopathological consequences of the use of these substances. Indeed, these drugs act on a range of neurotransmitter pathways/receptors whose imbalance has been associated with psychopathological conditions, including dopamine, cannabinoid CB1, GABA-A/B, 5-HT2A, glutamate, and k opioid receptors. An overall approach in terms of clinical management is briefly discussed. PMID:25655145

5 CFR 410.309 - Agreements to continue in service.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Agreements to continue in service. 410.309 Section 410.309 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS TRAINING Establishing and Implementing Training Programs § 410.309 Agreements to continue in service. (a...

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

PubMed

Peltoniemi, Marko A; Hagelberg, Nora M; Olkkola, Klaus T; Saari, Teijo I

2016-09-01

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Validity of suspected alcohol and drug violations in aviation employees.

PubMed

Li, Guohua; Brady, Joanne E; DiMaggio, Charles; Baker, Susan P; Rebok, George W

2010-10-01

In the United States, transportation employees who are suspected of using alcohol and drugs are subject to reasonable-cause testing. This study aims to assess the validity of suspected alcohol and drug violations in aviation employees. Using reasonable-cause testing and random testing data from the Federal Aviation Administration for the years 1995-2005, we calculated the positive predictive value (PPV) and positive likelihood ratio (LR+) of suspected alcohol and drug violations. The true status of violations was based on testing results, with an alcohol violation being defined as a blood alcohol concentration of ≥0.04 mg/dl and a drug violation as a test positive for marijuana, cocaine, amphetamines, phencyclidine or opiates. During the 11-year study period, a total of 2284 alcohol tests and 2015 drug tests were performed under the reasonable-cause testing program. The PPV was 37.7% [95% confidence interval (CI), 35.7-39.7%] for suspected alcohol violations and 12.6% (95% CI, 11.2-14.1%) for suspected drug violations. Random testing revealed an overall prevalence of 0.09% for alcohol violations and 0.6% for drug violations. The LR+ was 653.6 (95% CI, 581.7-734.3) for suspected alcohol violations and 22.5 (95% CI, 19.6-25.7) for suspected drug violations. The discriminative power of reasonable-cause testing suggests that, despite its limited positive predictive value, physical and behavioral observation represents an efficient screening method for detecting alcohol and drug violations. The limited positive predictive value of reasonable-cause testing in aviation employees is due in part to the very low prevalence of alcohol and drug violations. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Inducible Nitric Oxide Inhibitors Block NMDA Antagonist-Stimulated Motoric Behaviors and Medial Prefrontal Cortical Glutamate Efflux

PubMed Central

Bergstrom, Hadley C.; Darvesh, Altaf S.; Berger, S. P.

2015-01-01

Nitric oxide (NO) plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA)-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS) for studying the neurobehavioral effects of non-competitive NMDA-antagonist stimulants such as dizocilpine (MK-801) and phencyclidine (PCP). This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS) aminoguanidine (AG) and (-)-epigallocatechin-3-gallate (EGCG) in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG, or vehicle prior to receiving NMDA antagonists MK-801, PCP, or a conventional psychostimulant (cocaine) and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex (mPFC) was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated mPFC glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in “green tea” and chocolate) may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia. PMID:26696891

The neurotoxic effects of methamphetamine on 5-hydroxytryptamine and dopamine in brain: evidence for the protective effect of chlormethiazole.

PubMed

Green, A R; De Souza, R J; Williams, J L; Murray, T K; Cross, A J

1992-04-01

Studies were undertaken in mice and rats on the neurotoxic effects of methamphetamine on dopaminergic and 5-hydroxytryptaminergic neurones in the brain and the neuroprotective action of chlormethiazole. In initial studies, mice were injected with methamphetamine (5 mg/kg, i.p.) at 2 hr intervals, to a total of 4 times. This procedure produced a 66% loss of striatal dopamine and a 50% loss of tyrosine hydroxylase activity 3 days later. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each dose of methamphetamine, totally prevented the methamphetamine-induced loss of tyrosine hydroxylase activity and partly prevented the loss of dopamine. Phencyclidine (20 mg/kg, i.p.), given in place of chlormethiazole, also prevented the loss of tyrosine hydroxylase. Administration to rats of 4 doses of methamphetamine (15 mg/kg, i.p.) at 3 hr intervals resulted in a 75% loss of striatal dopamine 3 days later and a similar loss of 5-HT and 5-HIAA in cortex and hippocampus. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each injection of methamphetamine, protected against the loss of dopamine and indoleamine content, in the respective regions. Pentobarbital (25 mg/kg, i.p.) also provided substantial protection but diazepam (2.5 mg/kg, i.p.) was without effect. Confirming earlier studies, dizocilpine (1 mg/kg) also provided substantial protection against the methamphetamine-induced neurotoxicity. Preliminary data indicated that chlormethiazole was not neuroprotective because of a hypothermic action. These data therefore demonstrate that chlormethiazole is an effective neuroprotective agent against methamphetamine-induced neurotoxicity and extend the evidence for the possible value of this drug in preventing neurodegeneration.

Validity of Suspected Alcohol and Drug Violations in Aviation Employees

PubMed Central

Li, Guohua; Brady, Joanne E.; DiMaggio, Charles; Baker, Susan P.; Rebok, George W.

2012-01-01

Introduction In the United States, transportation employees who are suspected of using alcohol and drugs are subject to reasonable-cause testing. This study aims to assess the validity of suspected alcohol and drug violations in aviation employees. Methods Using reasonable-cause testing and random testing data from the Federal Aviation Administration for the years 1995 through 2005, we calculated the positive predictive value (PPV) and positive likelihood ratio (LR+) of suspected alcohol and drug violations. The true status of violations was based on testing results, with an alcohol violation being defined as a blood alcohol concentration of ≥40 mg/dL and a drug violation as a test positive for marijuana, cocaine, amphetamines, phencyclidine, or opiates. Results During the 11-year study period, a total of 2,284 alcohol tests and 2,015 drug tests were performed under the reasonable-cause testing program. The PPV was 37.7% [95% confidence interval (CI), 35.7–39.7%] for suspected alcohol violations and 12.6% (95% CI, 11.2–14.1%) for suspected drug violations. Random testing revealed an overall prevalence of 0.09% (601/649,796) for alcohol violations and 0.6% (7,211/1,130,922) for drug violations. The LR+ was 653.6 (95% CI, 581.7–734.3) for suspected alcohol violations and 22.5 (95% CI, 19.6–25.7) for suspected drug violations. Discussion The discriminative power of reasonable-cause testing suggests that, despite its limited positive predictive value, physical and behavioral observation represents an efficient screening method for detecting alcohol and drug violations. The limited positive predictive value of reasonable-cause testing in aviation employees is due in part to the very low prevalence of alcohol and drug violations. PMID:20712820

40 CFR 78.9 - Notice of the filing of petition for administrative review.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Notice of the filing of petition for administrative review. 78.9 Section 78.9 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPEAL PROCEDURES § 78.9 Notice of the filing of petition for administrative...

[Cost comparative analysis of drug therapy for non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer in Japan].

PubMed

Hashiguchi, Masayuki; Yamauchi, Nobuaki; Uchikura, Takeshi; Mochizuki, Mayumi

2008-04-01

Drug selection for the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer was analyzed pharmacoeconomically. Two patterns consisting of continuation of an NSAID plus administration of the prostaglandin (PG) preparation misoprostol (PG model) for 8 weeks and continuation of an NSAID plus administration of the proton-pump inhibitors omeprazole and lansoprazole (PPI model) for 8 weeks were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drugs and gastric ulcer, and cost-comparative analyses were conducted based on the number of persons who had ulcer healing as health outcomes. Costs were estimated with respect to health expenditures from the third-party payer (public) perspective. In the case of continuation of an NSAID plus administration of the proton-pump inhibitor omeprazole for 8 weeks, the health outcomes improved and costs were reduced in comparison with continuation of an NSAID plus administration of misoprostol, thus making the administration of omeprazole the dominant choice. With continuation of an NSAID plus administration of lansoprazole for 8 weeks, the cost-savings of lansoprazole were inferior to those of misoprostol. The generic omeprazole product was the most cost-saving among the four drugs (misoprostol, original omeprazole product, generic omeprazole product, and lansoprazole) examined.

Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, α1- and 5-HT2A-receptors

PubMed Central

Sebban, Claude; Tesolin-Decros, Brigitte; Ciprian-Ollivier, Jorge; Perret, Laurent; Spedding, Michael

2002-01-01

The electroencephalographic (EEG) effects of the propsychotic agent phencyclidine (PCP), were studied in conscious rats using power spectra (0 – 30 Hz), from the prefrontal cortex or sensorimotor cortex. PCP (0.1 – 3 mg kg−1 s.c.) caused a marked dose-dependent increase in EEG power in the frontal cortex at 1 – 3 Hz with decreases in power at higher frequencies (9 – 30 Hz). At high doses (3 mg kg−1 s.c.) the entire spectrum shifted to more positive values, indicating an increase in cortical synchronization. MK 801 (0.05 – 0.1 mg kg−1 i.p.) caused similar effects but with lesser changes in power. In contrast, the non-competitive AMPA antagonists GYKI 52466 and GYKI 53655 increased EEG power over the whole power spectrum (1 – 10 mg kg−1 i.p.) The atypical antipsychotic clozapine (0.2 mg kg−1 s.c.) synchronized the EEG (peak 8 Hz). The 5-HT2A-antagonist, M100907, specifically increased EEG power at 2 – 3 Hz at low doses (10 and 50 μg kg÷1 s.c.), whereas at higher doses (0.1 mg kg−1 s.c.) the profile resembled that of clozapine. Clozapine (0.2 mg kg−1 s.c.), GYKI 53655 (5 mg kg−1 i.p.), prazosin (0.05 and 0.1 mg kg−1 i.p.), and M100907 (0.01 and 0.05 mg kg−1 s.c.) antagonized the decrease in power between 5 and 30 Hz caused by PCP (1 mg kg−1 s.c.), but not the increase in power at 1 – 3 Hz in prefrontal cortex. PMID:11786481

5 CFR 890.1033 - Notice of suspension.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 890.1033 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care... suspension; and (6) The provider's rights to contest the suspension. ...

5 CFR 890.1033 - Notice of suspension.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 890.1033 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care... suspension; and (6) The provider's rights to contest the suspension. ...

Nitrates for stable angina: a systematic review and meta-analysis of randomized clinical trials.

PubMed

Wei, Jiafu; Wu, Taixiang; Yang, Qing; Chen, Mao; Ni, Juan; Huang, Dejia

2011-01-07

To assess the effect (harms and benefits) of nitrates for stable angina. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Randomized controlled trials with both parallel and crossover design were included. The following outcome measures were evaluated: number of angina attacks weekly and nitroglycerin consumption, quality of life, total exercise duration, time to onset of angina and time to 1 mm ST depression. Fifty-one trials with 3595 patients meeting inclusion criteria were analyzed. Both intermittent and continuous regimens of nitrates lengthened exercise duration significantly by 31 and 53 s respectively. The number of angina attacks was significantly reduced by 2.89 episodes weekly for continuous administration and 1.5 episodes weekly for intermittent administration. With intermittent administration, increased dose provided with 21 s more length of exercise duration. With continuous administration, exercise duration was pronged more in low-dose group. Quality of life was not improved by continuous application of GTN patches and was similar between continuous and intermittent groups. In addition, 51.6% patients receiving nitrates complained with headache. Long-term administration of nitrates was beneficial for angina prophylaxis and improved exercise performance but might be ineffective for improving quality of life. With continuous regimen, low-dose nitrates were more effective than high-dose ones for improving exercise performance. By contrast, with intermittent regimen, high-dose nitrates were more effective. In addition, intermittent administration could bring zero-hour effect. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

5 CFR 870.510 - Continuation of eligibility for former Federal employees of the Civilian Marksmanship Program.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Continuation of eligibility for former Federal employees of the Civilian Marksmanship Program. 870.510 Section 870.510 Administrative Personnel... LIFE INSURANCE PROGRAM Coverage § 870.510 Continuation of eligibility for former Federal employees of...

5 CFR 870.510 - Continuation of eligibility for former Federal employees of the Civilian Marksmanship Program.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Continuation of eligibility for former Federal employees of the Civilian Marksmanship Program. 870.510 Section 870.510 Administrative Personnel... LIFE INSURANCE PROGRAM Coverage § 870.510 Continuation of eligibility for former Federal employees of...

Freezing and thawing effects on fat, protein, and lactose levels of human natural milk administered by gavage and continuous infusion.

PubMed

Abranches, Andrea D; Soares, Fernanda V M; Junior, Saint-Clair G; Moreira, Maria Elisabeth L

2014-01-01

to analyze the changes in human milk macronutrients: fat, protein, and lactose in natural human milk (raw), frozen and thawed, after administration simulation by gavage and continuous infusion. an experimental study was performed with 34 human milk samples. The infrared spectrophotometry using the infrared analysis equipment MilkoScan Minor® (Foss, Denmark) equipment was used to analyze the macronutrients in human milk during the study phases. The analyses were performed in natural (raw) samples and after freezing and fast thawing following two steps: gavage and continuous infusion. The non-parametric Wilcoxon test for paired samples was used for the statistical analysis. the fat content was significantly reduced after administration by continuous infusion (p<0.001) during administration of both raw and thawed samples. No changes in protein and lactose content were observed between the two forms of infusion. However, the thawing process significantly increased the levels of lactose and milk protein. the route of administration by continuous infusion showed the greatest influence on fat loss among all the processes required for human milk administration. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

5 CFR 950.101 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... welfare organizations created to supply common fundraising, administrative, and management services to its... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SOLICITATION OF FEDERAL CIVILIAN AND UNIFORMED SERVICE PERSONNEL FOR CONTRIBUTIONS TO PRIVATE VOLUNTARY...

5 CFR 950.101 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... welfare organizations created to supply common fundraising, administrative, and management services to its... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SOLICITATION OF FEDERAL CIVILIAN AND UNIFORMED SERVICE PERSONNEL FOR CONTRIBUTIONS TO PRIVATE VOLUNTARY...

5 CFR 950.101 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... welfare organizations created to supply common fundraising, administrative, and management services to its... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SOLICITATION OF FEDERAL CIVILIAN AND UNIFORMED SERVICE PERSONNEL FOR CONTRIBUTIONS TO PRIVATE VOLUNTARY...

5 CFR 950.101 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... welfare organizations created to supply common fundraising, administrative, and management services to its... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SOLICITATION OF FEDERAL CIVILIAN AND UNIFORMED SERVICE PERSONNEL FOR CONTRIBUTIONS TO PRIVATE VOLUNTARY...

Continuous infusion or bolus injection of loop diuretics for congestive heart failure?

PubMed

Zepeda, Patricio; Rain, Carmen; Sepúlveda, Paola

2016-04-22

Loop diuretics are widely used in acute heart failure. However, there is controversy about the superiority of continuous infusion over bolus administration. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including 11 pertinent randomized controlled trials overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded continuous administration of loop diuretics probably reduces mortality and length of stay compared to intermittent administration in patients with acute heart failure.

Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Qi; Wan, Qilong; Yang, Rongtao

Highlights: Black-Right-Pointing-Pointer Different PTH administration exerts different effects on condylar chondrocyte. Black-Right-Pointing-Pointer Intermittent PTH administration suppresses condylar chondrocyte proliferation. Black-Right-Pointing-Pointer Continuous PTH administration maintains condylar chondrocyte proliferating. Black-Right-Pointing-Pointer Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presentedmore » enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular asymmetry.« less

5 CFR 890.1022 - Contesting proposed permissive debarments.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... 890.1022 Section 890.1022 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1022 Contesting proposed permissive debarments...

5 CFR 890.1022 - Contesting proposed permissive debarments.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... 890.1022 Section 890.1022 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1022 Contesting proposed permissive debarments...

Break-even Analysis: A Practical Tool for Administrators of Continuing Education.

ERIC Educational Resources Information Center

Noel, James

1982-01-01

Explains how break-even analysis can help the continuing education administrator in planning by clarifying the relationship between costs, volume, and surplus revenues. Also explains the concepts of fixed, variable, and semivariable costs. (CT)

5 CFR 890.1004 - Bases for mandatory debarments.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section 890.1004 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1004 Bases for mandatory debarments. (a) Debarment...

5 CFR 890.1011 - Bases for permissive debarments.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section 890.1011 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1011 Bases for permissive debarments. (a) Licensure...

Psychedelics and schizophrenia.

PubMed

González-Maeso, Javier; Sealfon, Stuart C

2009-04-01

Research on psychedelics such as lysergic acid diethylamide (LSD) and dissociative drugs such as phencyclidine (PCP) and the symptoms, neurochemical abnormalities and treatment of schizophrenia have converged. The effects of hallucinogenic drugs resemble some of the core symptoms of schizophrenia. Some atypical antipsychotic drugs were identified by their high affinity for serotonin 5-HT(2A) receptors, which is also the target of LSD-like drugs. Several effects of PCP-like drugs are strongly affected by both 5-HT(2A) and metabotropic glutamate 2/3 receptor modulation. A serotonin-glutamate receptor complex in cortical pyramidal neurons has been identified that might be the target both of psychedelics and the atypical and glutamate classes of antipsychotic drugs. Recent results on the receptor, signalling and circuit mechanisms underlying the response to psychedelic and antipsychotic drugs might lead to unification of the serotonin and glutamate neurochemical hypotheses of schizophrenia.

Platelet count recovery and seroreversion in immune HIT despite continuation of heparin: further observations and literature review.

PubMed

Shih, Andrew W; Sheppard, Jo-Ann I; Warkentin, Theodore E

2017-10-05

One of the standard distinctions between type 1 (non-immune) and type 2 (immune-mediated) heparin-induced thrombocytopenia (HIT) is the transience of thrombocytopenia: type 1 HIT is viewed as early-onset and transient thrombocytopenia, with platelet count recovery despite continuing heparin administration. In contrast, type 2 HIT is viewed as later-onset (i. e., 5 days or later) thrombocytopenia in which it is generally believed that platelet count recovery will not occur unless heparin is discontinued. However, older reports of type 2 HIT sometimes did include the unexpected observation that platelet counts could recover despite continued heparin administration, although without information provided regarding changes in HIT antibody levels in association with platelet count recovery. In recent years, some reports of type 2 HIT have confirmed the observation that platelet count recovery can occur despite continuing heparin administration, with serological evidence of waning levels of HIT antibodies ("seroreversion"). We now report two additional patient cases of type 2 HIT with platelet count recovery despite ongoing therapeutic-dose (1 case) or prophylactic-dose (1 case) heparin administration, in which we demonstrate concomitant waning of HIT antibody levels. We further review the literature describing this phenomenon of HIT antibody seroreversion and platelet count recovery despite continuing heparin administration. Our observations add to the concept that HIT represents a remarkably transient immune response, including sometimes even when heparin is continued.

PACS administrators' and radiologists' perspective on the importance of features for PACS selection.

PubMed

Joshi, Vivek; Narra, Vamsi R; Joshi, Kailash; Lee, Kyootai; Melson, David

2014-08-01

Picture archiving and communication systems (PACS) play a critical role in radiology. This paper presents the criteria important to PACS administrators for selecting a PACS. A set of criteria are identified and organized into an integrative hierarchical framework. Survey responses from 48 administrators are used to identify the relative weights of these criteria through an analytical hierarchy process. The five main dimensions for PACS selection in order of importance are system continuity and functionality, system performance and architecture, user interface for workflow management, user interface for image manipulation, and display quality. Among the subdimensions, the highest weights were assessed for security, backup, and continuity; tools for continuous performance monitoring; support for multispecialty images; and voice recognition/transcription. PACS administrators' preferences were generally in line with that of previously reported results for radiologists. Both groups assigned the highest priority to ensuring business continuity and preventing loss of data through features such as security, backup, downtime prevention, and tools for continuous PACS performance monitoring. PACS administrators' next high priorities were support for multispecialty images, image retrieval speeds from short-term and long-term storage, real-time monitoring, and architectural issues of compatibility and integration with other products. Thus, next to ensuring business continuity, administrators' focus was on issues that impact their ability to deliver services and support. On the other hand, radiologists gave high priorities to voice recognition, transcription, and reporting; structured reporting; and convenience and responsiveness in manipulation of images. Thus, radiologists' focus appears to be on issues that may impact their productivity, effort, and accuracy.

5 CFR 890.1302 - Duration.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Duration. 890.1302 Section 890.1302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Department of Defense Federal Employees Health Benefits Program...

5 CFR 890.1302 - Duration.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Duration. 890.1302 Section 890.1302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Department of Defense Federal Employees Health Benefits Program...

5 CFR 890.1302 - Duration.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Duration. 890.1302 Section 890.1302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Department of Defense Federal Employees Health Benefits Program...

5 CFR 890.1302 - Duration.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Duration. 890.1302 Section 890.1302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Department of Defense Federal Employees Health Benefits Program...

29 CFR 1912.8 - Committee charters.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) ADVISORY COMMITTEES ON STANDARDS Organizational Matters § 1912.8 Committee charters. (a) Filing. No... responsible for providing support (i.e., the Occupational Safety and Health Administration); (6) Description...

29 CFR 1912.8 - Committee charters.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) ADVISORY COMMITTEES ON STANDARDS Organizational Matters § 1912.8 Committee charters. (a) Filing. No... responsible for providing support (i.e., the Occupational Safety and Health Administration); (6) Description...

47 CFR 54.707 - Audit controls.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 3 2014-10-01 2014-10-01 false Audit controls. 54.707 Section 54.707 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Administration § 54.707 Audit controls. The Administrator shall have authority to audit...

47 CFR 54.707 - Audit controls.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 3 2011-10-01 2011-10-01 false Audit controls. 54.707 Section 54.707 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Administration § 54.707 Audit controls. The Administrator shall have authority to audit...

47 CFR 54.707 - Audit controls.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 3 2013-10-01 2013-10-01 false Audit controls. 54.707 Section 54.707 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Administration § 54.707 Audit controls. The Administrator shall have authority to audit...

47 CFR 54.707 - Audit controls.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 3 2010-10-01 2010-10-01 false Audit controls. 54.707 Section 54.707 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Administration § 54.707 Audit controls. The Administrator shall have authority to audit...

5 CFR 842.804 - Evidence.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Evidence. 842.804 Section 842.804 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air Traffic...

5 CFR 842.805 - Withholding and contributions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Withholding and contributions. 842.805 Section 842.805 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers...

5 CFR 842.804 - Evidence.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Evidence. 842.804 Section 842.804 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air Traffic...

5 CFR 842.804 - Evidence.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Evidence. 842.804 Section 842.804 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air Traffic...

5 CFR 842.805 - Withholding and contributions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Withholding and contributions. 842.805 Section 842.805 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers...

5 CFR 842.805 - Withholding and contributions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Withholding and contributions. 842.805 Section 842.805 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers...

5 CFR 842.804 - Evidence.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Evidence. 842.804 Section 842.804 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air Traffic...

5 CFR 842.805 - Withholding and contributions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Withholding and contributions. 842.805 Section 842.805 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers...

5 CFR 842.805 - Withholding and contributions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Withholding and contributions. 842.805 Section 842.805 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers...

5 CFR 842.804 - Evidence.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Evidence. 842.804 Section 842.804 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air Traffic...

The Intuitive Principal: A Guide to Leadership.

ERIC Educational Resources Information Center

Dyer, Karen M.; Carothers, Jacqueline

Professional demands on school administrators continue to multiply exponentially. Effective administrators require solid preparation programs, continuing professional development, extensive experience, mentoring, and the support of supervisor and school colleagues. Chapter 1, "Intuitive Ways of Knowing," references research on intuition,…

5 CFR 890.1009 - Contesting proposed mandatory debarments.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... 890.1009 Section 890.1009 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1009 Contesting proposed mandatory debarments. (a...

5 CFR 890.1009 - Contesting proposed mandatory debarments.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... 890.1009 Section 890.1009 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1009 Contesting proposed mandatory debarments. (a...

5 CFR 890.1009 - Contesting proposed mandatory debarments.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... 890.1009 Section 890.1009 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1009 Contesting proposed mandatory debarments. (a...

5 CFR 919.995 - Principal.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Principal. 919.995 Section 919.995 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 919.995 Principal. Principal means— (a) An...

5 CFR 930.103 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 930.103 Section 930.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Motor Vehicle Operators § 930.103 Coverage...

5 CFR 930.103 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Coverage. 930.103 Section 930.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Motor Vehicle Operators § 930.103 Coverage...

5 CFR 930.103 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 930.103 Section 930.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Motor Vehicle Operators § 930.103 Coverage...

5 CFR 930.103 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 930.103 Section 930.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Motor Vehicle Operators § 930.103 Coverage...

5 CFR 930.103 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 930.103 Section 930.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROGRAMS FOR SPECIFIC POSITIONS AND EXAMINATIONS (MISCELLANEOUS) Motor Vehicle Operators § 930.103 Coverage...

5 CFR 831.617 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false [Reserved] 831.617 Section 831.617 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Survivor Annuities Elections at the Time of Retirement § 831.617 [Reserved] ...

5 CFR 831.615 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false [Reserved] 831.615 Section 831.615 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Survivor Annuities Elections at the Time of Retirement § 831.615 [Reserved] ...

5 CFR 890.1014 - Notice of proposed permissive debarment.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... 890.1014 Section 890.1014 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1014 Notice of proposed permissive debarment...

5 CFR 890.910 - Provider information.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Provider information. 890.910 Section 890.910 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Limit on Inpatient Hospital Charges, Physician Charges...

5 CFR 890.1014 - Notice of proposed permissive debarment.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... 890.1014 Section 890.1014 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1014 Notice of proposed permissive debarment...

5 CFR 890.910 - Provider information.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Provider information. 890.910 Section 890.910 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Limit on Inpatient Hospital Charges, Physician Charges...

5 CFR 890.1014 - Notice of proposed permissive debarment.

Code of Federal Regulations, 2012 CFR

2012-01-01

.... 890.1014 Section 890.1014 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1014 Notice of proposed permissive debarment...

5 CFR 890.1014 - Notice of proposed permissive debarment.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... 890.1014 Section 890.1014 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1014 Notice of proposed permissive debarment...

5 CFR 890.910 - Provider information.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Provider information. 890.910 Section 890.910 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Limit on Inpatient Hospital Charges, Physician Charges...

5 CFR 890.1014 - Notice of proposed permissive debarment.

Code of Federal Regulations, 2011 CFR

2011-01-01

.... 890.1014 Section 890.1014 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1014 Notice of proposed permissive debarment...

5 CFR 890.910 - Provider information.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Provider information. 890.910 Section 890.910 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Limit on Inpatient Hospital Charges, Physician Charges...

14 CFR 125.111 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... airplane powered by airplane engines rated at more than 600 horsepower each for maximum continuous... would not contribute materially to the objective sought, the Administrator may require compliance with...

49 CFR 1503.203 - Investigations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY ADMINISTRATIVE AND PROCEDURAL RULES INVESTIGATIVE AND ENFORCEMENT PROCEDURES... Chief Counsel, the Assistant Administrator for Security Operations, the Assistant Administrator for...

28 CFR 42.410 - Continuing State programs.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 1 2014-07-01 2014-07-01 false Continuing State programs. 42.410 Section 42.410 Judicial Administration DEPARTMENT OF JUSTICE NONDISCRIMINATION; EQUAL EMPLOYMENT OPPORTUNITY; POLICIES AND PROCEDURES Coordination of Enforcement of Non-discrimination in Federally Assisted Programs...

5 CFR 890.604 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false [Reserved] 890.604 Section 890.604 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.604...

5 CFR 890.604 - [Reserved

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false [Reserved] 890.604 Section 890.604 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.604...

40 CFR 142.50 - Requirements for an exemption.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Section 142.50 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Exemptions Issued by the Administrator § 142.50 Requirements for an exemption. (a) The Administrator may exempt any public water system within...

40 CFR 142.50 - Requirements for an exemption.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Section 142.50 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Exemptions Issued by the Administrator § 142.50 Requirements for an exemption. (a) The Administrator may exempt any public water system within...

40 CFR 142.50 - Requirements for an exemption.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Section 142.50 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Exemptions Issued by the Administrator § 142.50 Requirements for an exemption. (a) The Administrator may exempt any public water system within...

40 CFR 142.50 - Requirements for an exemption.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Section 142.50 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Exemptions Issued by the Administrator § 142.50 Requirements for an exemption. (a) The Administrator may exempt any public water system within...

40 CFR 142.50 - Requirements for an exemption.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Section 142.50 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Exemptions Issued by the Administrator § 142.50 Requirements for an exemption. (a) The Administrator may exempt any public water system within...

5 CFR 890.801 - Introduction.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Introduction. 890.801 Section 890.801 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for Former Spouses § 890.801 Introduction. This subpart sets...

5 CFR 720.307 - Interagency report clearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Interagency report clearance. 720.307 Section 720.307 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) AFFIRMATIVE EMPLOYMENT PROGRAMS Disabled Veterans Affirmative Action Program § 720.307...

5 CFR 900.601 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED... governments and encourages innovation and allows for diversity among State and local governments in the design, execution, and management of their systems of personnel administration, as provided by that Act. (b) Certain...

5 CFR 831.602 - Relation to other regulations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Relation to other regulations. 831.602 Section 831.602 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Survivor Annuities Organization and Structure of Regulations on Survivor...

5 CFR 831.601 - Purpose and scope.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Purpose and scope. 831.601 Section 831.601 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Survivor Annuities Organization and Structure of Regulations on Survivor Annuities...

5 CFR 850.302 - Record maintenance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Record maintenance. 850.302 Section 850.302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT SYSTEMS MODERNIZATION Records § 850.302 Record maintenance. (a) The retirement and...

5 CFR 850.302 - Record maintenance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Record maintenance. 850.302 Section 850.302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT SYSTEMS MODERNIZATION Records § 850.302 Record maintenance. (a) The retirement and...

5 CFR 850.302 - Record maintenance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Record maintenance. 850.302 Section 850.302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT SYSTEMS MODERNIZATION Records § 850.302 Record maintenance. (a) The retirement and...

5 CFR 850.302 - Record maintenance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Record maintenance. 850.302 Section 850.302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT SYSTEMS MODERNIZATION Records § 850.302 Record maintenance. (a) The retirement and...

5 CFR 831.1201 - Introduction.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Introduction. 831.1201 Section 831.1201 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1201 Introduction. This subpart sets out the requirements an employee...

5 CFR 831.406 - Withdrawal of voluntary contributions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Withdrawal of voluntary contributions. 831.406 Section 831.406 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Voluntary Contributions § 831.406 Withdrawal of voluntary...

5 CFR 731.601 - Savings provision.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Savings provision. 731.601 Section 731.601 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Savings Provision § 731.601 Savings provision. No provision of the regulations in...

5 CFR 831.406 - Withdrawal of voluntary contributions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Withdrawal of voluntary contributions. 831.406 Section 831.406 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Voluntary Contributions § 831.406 Withdrawal of voluntary...

5 CFR 831.402 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Definitions. 831.402 Section 831.402 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Voluntary Contributions § 831.402 Definitions. In this subpart: Applicant for retirement means a...

5 CFR 831.1201 - Introduction.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Introduction. 831.1201 Section 831.1201 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1201 Introduction. This subpart sets out the requirements an employee...

5 CFR 831.1205 - Agency-filed disability retirement applications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Agency-filed disability retirement applications. 831.1205 Section 831.1205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1205 Agency-filed...

5 CFR 831.1004 - Agency contributions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Agency contributions. 831.1004 Section 831.1004 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT CSRS Offset § 831.1004 Agency contributions. The employing agency, the Secretary of...

5 CFR 831.1207 - Withdrawal of disability retirement applications.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Withdrawal of disability retirement applications. 831.1207 Section 831.1207 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1207 Withdrawal of...

5 CFR 831.402 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Definitions. 831.402 Section 831.402 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Voluntary Contributions § 831.402 Definitions. In this subpart: Applicant for retirement means a...

5 CFR 731.601 - Savings provision.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Savings provision. 731.601 Section 731.601 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Savings Provision § 731.601 Savings provision. No provision of the regulations in...

5 CFR 831.1205 - Agency-filed disability retirement applications.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Agency-filed disability retirement applications. 831.1205 Section 831.1205 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1205 Agency-filed...

5 CFR 831.1004 - Agency contributions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Agency contributions. 831.1004 Section 831.1004 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT CSRS Offset § 831.1004 Agency contributions. The employing agency, the Secretary of...

5 CFR 831.1002 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Definitions. 831.1002 Section 831.1002 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT CSRS Offset § 831.1002 Definitions. Contribution and benefit base means the contribution and...

5 CFR 831.1002 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Definitions. 831.1002 Section 831.1002 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT CSRS Offset § 831.1002 Definitions. Contribution and benefit base means the contribution and...

5 CFR 831.1001 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Purpose. 831.1001 Section 831.1001 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT CSRS Offset § 831.1001 Purpose. This subpart sets forth the provisions concerning employees and...

5 CFR 831.1001 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Purpose. 831.1001 Section 831.1001 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT CSRS Offset § 831.1001 Purpose. This subpart sets forth the provisions concerning employees and...

5 CFR 720.302 - Definition.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Definition. 720.302 Section 720.302 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) AFFIRMATIVE EMPLOYMENT PROGRAMS Disabled Veterans Affirmative Action Program § 720.302 Definition. As used in...

5 CFR 911.103 - Eligibility for indemnification.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Eligibility for indemnification. 911.103 Section 911.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.103 Eligibility...

5 CFR 911.103 - Eligibility for indemnification.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Eligibility for indemnification. 911.103 Section 911.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.103 Eligibility...

5 CFR 911.103 - Eligibility for indemnification.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Eligibility for indemnification. 911.103 Section 911.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.103 Eligibility...

5 CFR 911.102 - General definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false General definitions. 911.102 Section 911.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.102 General definitions. In...

5 CFR 911.102 - General definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false General definitions. 911.102 Section 911.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.102 General definitions. In...

5 CFR 911.102 - General definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false General definitions. 911.102 Section 911.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.102 General definitions. In...

5 CFR 911.103 - Eligibility for indemnification.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Eligibility for indemnification. 911.103 Section 911.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.103 Eligibility...

5 CFR 911.102 - General definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false General definitions. 911.102 Section 911.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.102 General definitions. In...

5 CFR 911.103 - Eligibility for indemnification.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Eligibility for indemnification. 911.103 Section 911.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.103 Eligibility...

5 CFR 911.102 - General definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false General definitions. 911.102 Section 911.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) PROCEDURES FOR STATES AND LOCALITIES TO REQUEST INDEMNIFICATION § 911.102 General definitions. In...

29 CFR 1949.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 9 2011-07-01 2011-07-01 false Definitions. 1949.2 Section 1949.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OFFICE OF TRAINING AND EDUCATION, OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION OSHA Training Institute...

29 CFR 1949.5 - Refunds.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 9 2011-07-01 2011-07-01 false Refunds. 1949.5 Section 1949.5 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OFFICE OF TRAINING AND EDUCATION, OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION OSHA Training Institute...

29 CFR 1949.5 - Refunds.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Refunds. 1949.5 Section 1949.5 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OFFICE OF TRAINING AND EDUCATION, OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION OSHA Training Institute...

29 CFR 1979.101 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED... Occupational Safety and Health Administration of the United States Department of Labor. Person means one or... transportation. Assistant Secretary means the Assistant Secretary of Labor for Occupational Safety and Health or...

29 CFR 1949.1 - Policy regarding tuition fees.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OFFICE OF TRAINING AND EDUCATION, OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION OSHA Training... safety and health program. Individuals or organizations wishing to be considered for this exemption shall...

29 CFR 1949.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Definitions. 1949.2 Section 1949.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OFFICE OF TRAINING AND EDUCATION, OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION OSHA Training Institute...

29 CFR 1949.1 - Policy regarding tuition fees.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OFFICE OF TRAINING AND EDUCATION, OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION OSHA Training... safety and health program. Individuals or organizations wishing to be considered for this exemption shall...

29 CFR 1979.101 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED... Occupational Safety and Health Administration of the United States Department of Labor. Person means one or... transportation. Assistant Secretary means the Assistant Secretary of Labor for Occupational Safety and Health or...

5 CFR 831.905 - Evidence.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Evidence. 831.905 Section 831.905 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.905 Evidence. (a) An agency head's determination...

5 CFR 831.907 - Withholdings and contributions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Withholdings and contributions. 831.907 Section 831.907 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.907 Withholdings and...

5 CFR 842.807 - Review of decisions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Review of decisions. 842.807 Section 842.807 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air...

5 CFR 831.909 - Reemployment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Reemployment. 831.909 Section 831.909 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.909 Reemployment. An employee who has been...

5 CFR 831.905 - Evidence.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Evidence. 831.905 Section 831.905 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.905 Evidence. (a) An agency head's determination...

5 CFR 831.909 - Reemployment.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Reemployment. 831.909 Section 831.909 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.909 Reemployment. An employee who has been...

5 CFR 831.907 - Withholdings and contributions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Withholdings and contributions. 831.907 Section 831.907 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.907 Withholdings and...

5 CFR 831.905 - Evidence.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Evidence. 831.905 Section 831.905 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.905 Evidence. (a) An agency head's determination...

5 CFR 842.807 - Review of decisions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Review of decisions. 842.807 Section 842.807 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air...

5 CFR 842.807 - Review of decisions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Review of decisions. 842.807 Section 842.807 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air...

5 CFR 831.907 - Withholdings and contributions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Withholdings and contributions. 831.907 Section 831.907 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.907 Withholdings and...

5 CFR 842.807 - Review of decisions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Review of decisions. 842.807 Section 842.807 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air...

5 CFR 831.909 - Reemployment.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Reemployment. 831.909 Section 831.909 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.909 Reemployment. An employee who has been...

5 CFR 831.905 - Evidence.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Evidence. 831.905 Section 831.905 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.905 Evidence. (a) An agency head's determination...

5 CFR 831.909 - Reemployment.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Reemployment. 831.909 Section 831.909 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.909 Reemployment. An employee who has been...

5 CFR 831.905 - Evidence.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Evidence. 831.905 Section 831.905 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.905 Evidence. (a) An agency head's determination...

5 CFR 831.907 - Withholdings and contributions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Withholdings and contributions. 831.907 Section 831.907 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.907 Withholdings and...

5 CFR 831.907 - Withholdings and contributions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Withholdings and contributions. 831.907 Section 831.907 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.907 Withholdings and...

5 CFR 831.909 - Reemployment.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Reemployment. 831.909 Section 831.909 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Law Enforcement Officers and Firefighters § 831.909 Reemployment. An employee who has been...

5 CFR 842.807 - Review of decisions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Review of decisions. 842.807 Section 842.807 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-BASIC ANNUITY Law Enforcement Officers, Firefighters, and Air...

5 CFR 792.103 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 792.103 Section 792.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES' HEALTH, COUNSELING, AND WORK/LIFE PROGRAMS Alcoholism and Drug Abuse Programs and Services for...

5 CFR 792.103 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 792.103 Section 792.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES' HEALTH AND COUNSELING PROGRAMS Regulatory Requirements for Alcoholism and Drug Abuse Programs and...

5 CFR 792.103 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 792.103 Section 792.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES' HEALTH AND COUNSELING PROGRAMS Regulatory Requirements for Alcoholism and Drug Abuse Programs and...

5 CFR 792.103 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Coverage. 792.103 Section 792.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES' HEALTH AND COUNSELING PROGRAMS Regulatory Requirements for Alcoholism and Drug Abuse Programs and...

5 CFR 792.103 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 792.103 Section 792.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES' HEALTH, COUNSELING, AND WORK/LIFE PROGRAMS Alcoholism and Drug Abuse Programs and Services for...

5 CFR 890.1007 - Minimum length of mandatory debarments.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... 890.1007 Section 890.1007 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1007 Minimum length of mandatory debarments. (a...

5 CFR 890.604 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false [Reserved] 890.604 Section 890.604 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.604...

5 CFR 890.1007 - Minimum length of mandatory debarments.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... 890.1007 Section 890.1007 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1007 Minimum length of mandatory debarments. (a...

5 CFR 890.604 - [Reserved

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false [Reserved] 890.604 Section 890.604 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.604...

5 CFR 890.1010 - Debarring official's decision of contest.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... 890.1010 Section 890.1010 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1010 Debarring official's decision of contest. (a...

5 CFR 890.1007 - Minimum length of mandatory debarments.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... 890.1007 Section 890.1007 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1007 Minimum length of mandatory debarments. (a...

5 CFR 890.604 - [Reserved

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false [Reserved] 890.604 Section 890.604 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.604...

5 CFR 890.1028 - Conducting a fact-finding proceeding.

Code of Federal Regulations, 2013 CFR

2013-01-01

....1028 Section 890.1028 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Permissive Debarments § 890.1028 Conducting a fact-finding proceeding. (a) Informal...

5 CFR 890.1010 - Debarring official's decision of contest.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... 890.1010 Section 890.1010 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1010 Debarring official's decision of contest. (a...

5 CFR 890.1010 - Debarring official's decision of contest.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... 890.1010 Section 890.1010 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Mandatory Debarments § 890.1010 Debarring official's decision of contest. (a...

5 CFR 752.301 - Principal statutory requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Principal statutory requirements. 752.301 Section 752.301 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) ADVERSE ACTIONS (Eff. until 2-2-10) Principal Statutory Requirements for Removal...

5 CFR 732.101 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Purpose. 732.101 Section 732.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.101 Purpose. This part sets forth certain requirements and...

5 CFR 732.101 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Purpose. 732.101 Section 732.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.101 Purpose. This part sets forth certain requirements and...

5 CFR 732.102 - Definition and applicability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Definition and applicability. 732.102 Section 732.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.102 Definition and applicability. (a) For...

5 CFR 731.102 - Implementation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Implementation. 731.102 Section 731.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Scope § 731.102 Implementation. (a) An investigation conducted for the purpose of determining...

5 CFR 731.102 - Implementation.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Implementation. 731.102 Section 731.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Scope § 731.102 Implementation. (a) An investigation conducted for the purpose of determining...

5 CFR 732.102 - Definition and applicability.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Definition and applicability. 732.102 Section 732.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.102 Definition and applicability. (a) For...

5 CFR 732.102 - Definition and applicability.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Definition and applicability. 732.102 Section 732.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.102 Definition and applicability. (a) For...

5 CFR 731.102 - Implementation.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Implementation. 731.102 Section 731.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Scope § 731.102 Implementation. (a) An investigation conducted for the purpose of determining...

5 CFR 731.102 - Implementation.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Implementation. 731.102 Section 731.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Scope § 731.102 Implementation. (a) An investigation conducted for the purpose of determining...

5 CFR 732.102 - Definition and applicability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Definition and applicability. 732.102 Section 732.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.102 Definition and applicability. (a) For...

5 CFR 732.101 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Purpose. 732.101 Section 732.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.101 Purpose. This part sets forth certain requirements and...

5 CFR 732.102 - Definition and applicability.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Definition and applicability. 732.102 Section 732.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.102 Definition and applicability. (a) For...

5 CFR 732.101 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Purpose. 732.101 Section 732.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.101 Purpose. This part sets forth certain requirements and...

5 CFR 731.102 - Implementation.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Implementation. 731.102 Section 731.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) SUITABILITY Scope § 731.102 Implementation. (a) An investigation conducted for the purpose of determining...

5 CFR 732.101 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Purpose. 732.101 Section 732.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NATIONAL SECURITY POSITIONS Scope § 732.101 Purpose. This part sets forth certain requirements and...

5 CFR 730.103 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 730.103 Section 730.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NOTIFICATION OF POST-EMPLOYMENT RESTRICTIONS § 730.103 Coverage. (a) The following individuals are subject to...

5 CFR 730.103 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 730.103 Section 730.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NOTIFICATION OF POST-EMPLOYMENT RESTRICTIONS § 730.103 Coverage. (a) The following individuals are subject to...

5 CFR 730.103 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Coverage. 730.103 Section 730.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NOTIFICATION OF POST-EMPLOYMENT RESTRICTIONS § 730.103 Coverage. (a) The following individuals are subject to...

5 CFR 730.103 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 730.103 Section 730.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NOTIFICATION OF POST-EMPLOYMENT RESTRICTIONS § 730.103 Coverage. (a) The following individuals are subject to...

5 CFR 730.103 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 730.103 Section 730.103 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) NOTIFICATION OF POST-EMPLOYMENT RESTRICTIONS § 730.103 Coverage. (a) The following individuals are subject to...

5 CFR 919.920 - Civil judgment.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Civil judgment. 919.920 Section 919.920 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 919.920 Civil judgment. Civil judgment...

5 CFR 919.920 - Civil judgment.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Civil judgment. 919.920 Section 919.920 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 919.920 Civil judgment. Civil judgment...

5 CFR 919.920 - Civil judgment.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Civil judgment. 919.920 Section 919.920 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 919.920 Civil judgment. Civil judgment...

5 CFR 919.920 - Civil judgment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Civil judgment. 919.920 Section 919.920 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 919.920 Civil judgment. Civil judgment...

5 CFR 919.920 - Civil judgment.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Civil judgment. 919.920 Section 919.920 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 919.920 Civil judgment. Civil judgment...

5 CFR 890.1061 - Bases for penalties and assessments.

Code of Federal Regulations, 2014 CFR

2014-01-01

....1061 Section 890.1061 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Administrative Sanctions Imposed Against Health Care Providers Civil Monetary Penalties and Financial Assessments § 890.1061 Bases for penalties...

5 CFR 724.105 - Compliance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Compliance. 724.105 Section 724.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED... 2002 Reimbursement of Judgement Fund § 724.105 Compliance. An agency's failure to reimburse the...

5 CFR 724.105 - Compliance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Compliance. 724.105 Section 724.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED... 2002 Reimbursement of Judgement Fund § 724.105 Compliance. An agency's failure to reimburse the...

5 CFR 930.211 - Actions against administrative law judges.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Actions against administrative law judges. 930.211 Section 930.211 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.211 Actions against administrative law judges. (a) Procedures. An agency...

5 CFR 930.211 - Actions against administrative law judges.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Actions against administrative law judges. 930.211 Section 930.211 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.211 Actions against administrative law judges. (a) Procedures. An agency...

5 CFR 930.209 - Senior Administrative Law Judge Program.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Senior Administrative Law Judge Program. 930.209 Section 930.209 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.209 Senior Administrative Law Judge Program. (a) OPM administers a Senior...

5 CFR 930.209 - Senior Administrative Law Judge Program.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Senior Administrative Law Judge Program. 930.209 Section 930.209 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.209 Senior Administrative Law Judge Program. (a) OPM administers a Senior...

5 CFR 930.211 - Actions against administrative law judges.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Actions against administrative law judges. 930.211 Section 930.211 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.211 Actions against administrative law judges. (a) Procedures. An agency...

5 CFR 930.209 - Senior Administrative Law Judge Program.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Senior Administrative Law Judge Program. 930.209 Section 930.209 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.209 Senior Administrative Law Judge Program. (a) OPM administers a Senior...

5 CFR 930.211 - Actions against administrative law judges.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Actions against administrative law judges. 930.211 Section 930.211 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL...) Administrative Law Judge Program § 930.211 Actions against administrative law judges. (a) Procedures. An agency...

47 CFR 52.26 - NANC Recommendations on Local Number Portability Administration.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Portability Administration. 52.26 Section 52.26 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Number Portability Administration. (a) Local number portability administration shall comply with the... prepared by the NANC's Local Number Portability Administration Selection Working Group, dated April 25...

47 CFR 52.26 - NANC Recommendations on Local Number Portability Administration.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Portability Administration. 52.26 Section 52.26 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Number Portability Administration. (a) Local number portability administration shall comply with the... prepared by the NANC's Local Number Portability Administration Selection Working Group, dated April 25...

5 CFR 890.802 - Definition.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Definition. 890.802 Section 890.802 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for Former Spouses § 890.802 Definition. In this subpart, a...

5 CFR 890.305 - Reinstatement of enrollment after military service.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Reinstatement of enrollment after military service. 890.305 Section 890.305 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Enrollment § 890...

5 CFR 890.603 - Effective date.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Effective date. 890.603 Section 890.603 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.603...

5 CFR 890.802 - Definition.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Definition. 890.802 Section 890.802 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for Former Spouses § 890.802 Definition. In this subpart, a...

5 CFR 890.802 - Definition.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Definition. 890.802 Section 890.802 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for Former Spouses § 890.802 Definition. In this subpart, a...

5 CFR 890.305 - Reinstatement of enrollment after military service.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Reinstatement of enrollment after military service. 890.305 Section 890.305 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Enrollment § 890...

5 CFR 890.603 - Effective date.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Effective date. 890.603 Section 890.603 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Transfers From Retired Federal Employees Health Benefits Program § 890.603...

5 CFR 890.802 - Definition.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Definition. 890.802 Section 890.802 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for Former Spouses § 890.802 Definition. In this subpart, a...

5 CFR 838.1018 - Settlements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Settlements. 838.1018 Section 838.1018 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) COURT... Settlements. The former spouse may request that an amount be withheld from the retirement benefits that is...

5 CFR 843.405 - Dependency.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Dependency. 843.405 Section 843.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEATH BENEFITS AND EMPLOYEE REFUNDS Child Annuities § 843.405 Dependency. To be...

5 CFR 843.405 - Dependency.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Dependency. 843.405 Section 843.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEATH BENEFITS AND EMPLOYEE REFUNDS Child Annuities § 843.405 Dependency. To be...

5 CFR 843.405 - Dependency.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Dependency. 843.405 Section 843.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEATH BENEFITS AND EMPLOYEE REFUNDS Child Annuities § 843.405 Dependency. To be...

5 CFR 843.405 - Dependency.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Dependency. 843.405 Section 843.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEATH BENEFITS AND EMPLOYEE REFUNDS Child Annuities § 843.405 Dependency. To be...

5 CFR 843.405 - Dependency.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Dependency. 843.405 Section 843.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEATH BENEFITS AND EMPLOYEE REFUNDS Child Annuities § 843.405 Dependency. To be...

5 CFR 837.804 - Finality of elections under this subpart.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Finality of elections under this subpart. 837.804 Section 837.804 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) REEMPLOYMENT OF ANNUITANTS Alternative Entitlements and Canceled...

5 CFR 890.1210 - Reconsideration and appeal rights.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Reconsideration and appeal rights. 890.1210 Section 890.1210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for United States Hostages in Iraq...

5 CFR 890.1210 - Reconsideration and appeal rights.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Reconsideration and appeal rights. 890.1210 Section 890.1210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for United States Hostages in Iraq...

5 CFR 845.402 - Scope.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Scope. 845.402 Section 845.402 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEBT COLLECTION Agency Requests to OPM for Recovery of a Debt From the Civil...

5 CFR 845.402 - Scope.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Scope. 845.402 Section 845.402 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEBT COLLECTION Agency Requests to OPM for Recovery of a Debt From the Civil...

5 CFR 845.402 - Scope.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Scope. 845.402 Section 845.402 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES RETIREMENT SYSTEM-DEBT COLLECTION Agency Requests to OPM for Recovery of a Debt From the Civil...