Sample records for phencyclidine

  1. Substance use - phencyclidine (PCP)

    MedlinePlus

    PCP; Substance abuse - phencyclidine; Drug abuse - phencyclidine; Drug use - phencyclidine ... PCP is a mind-altering drug. This means it acts on your brain (central nervous system) and changes your mood, behavior, and the way you relate to ...

  2. Bias of phencyclidine discrimination by the schedule of reinforcement.

    PubMed Central

    McMillan, D E; Wenger, G R

    1984-01-01

    Pigeons, trained to discriminate phencyclidine from saline under a procedure requiring the bird to track the location of a color, received cumulative doses of phencyclidine, pentobarbital, or d-amphetamine with a variety of schedules of reinforcement in effect (across phases). When the same second-order schedules were used to reinforce responding after either saline or phencyclidine administration, stimulus control by phencyclidine did not depend on the schedule parameter. When different second-order schedules were used that biased responding toward the phencyclidine-correlated key color, pigeons responded on the phencyclidine-correlated key at lower doses of phencyclidine and pentobarbital than when the second-order schedule biased responding toward the saline key color. A similar but less marked effect was obtained with d-amphetamine. Attempts to produce bias by changing reinforcement magnitude (duration of food availability) were less successful. A signal-detection analysis of dose-effect curves for phencyclidine under two of the second-order schedules employed suggested that at low doses of phencyclidine, response bias is a major determinant of responding. As doses were increased, position preferences occurred and response bias decreased; at higher doses both response bias and position preference decreased and discriminability increased. With low doses of pentobarbital, responding again was biased but increasing doses produced position preference with only small increases in discriminability. At low doses of d-amphetamine responding also was biased, but bias did not decrease consistently with dose nor did discriminability increase. These experiments suggest that the schedule of reinforcement can be used to bias responding toward or away from making the drug-correlated response in drug discrimination experiments, and that signal-detection analysis and analysis of responding at a position can be used to separate the discriminability of the drug state from other effects of the drug on responding. PMID:6481300

  3. Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil.

    PubMed

    Seeman, Philip; Guan, Hong-Chang; Hirbec, Hélène

    2009-08-01

    Although it is commonly stated that phencyclidine is an antagonist at ionotropic glutamate receptors, there has been little measure of its potency on other receptors in brain tissue. Although we previously reported that phencyclidine stimulated cloned-dopamine D2Long and D2Short receptors, others reported that phencyclidine did not stimulate D2 receptors in homogenates of rat brain striatum. This study, therefore, examined whether phencyclidine and other hallucinogens and psychostimulants could stimulate the incorporation of [(35)S]GTP-gamma-S into D2 receptors in homogenates of rat brain striatum, using the same conditions as previously used to study the cloned D2 receptors. Using 10 microM dopamine to define 100% stimulation, phencyclidine elicited a maximum incorporation of 46% in rat striata, with a half-maximum concentration of 70 nM for phencyclidine, when compared with 80 nM for dopamine, 89 nM for salvinorin A (48 nM for D2Long), 105 nM for lysergic acid diethylamide (LSD), 120 nM for R-modafinil, 710 nM for dizocilpine, 1030 nM for ketamine, and >10,000 nM for S-modafinil. These compounds also inhibited the binding of the D2-selective ligand [(3)H]domperidone. The incorporation was inhibited by the presence of 200 microM guanylylimidodiphosphate and also by D2 blockade, using 10 microM S-sulpiride, but not by D1 blockade with 10 microM SCH23390. Hypertonic buffer containing 150 mM NaCl inhibited the stimulation by phencyclidine, which may explain negative results by others. It is concluded that phencyclidine and other psychostimulants and hallucinogens can stimulate dopamine D2 receptors at concentrations related to their behavioral actions.

  4. Phencyclidine-induced malignant hyperthermia causing submassive liver necrosis.

    PubMed

    Armen, R; Kanel, G; Reynolds, T

    1984-07-01

    This report describes three male patients arrested for aggressive and combative behavior, characteristic of phencyclidine intoxication, in whom severe hyperthermia, respiratory failure, and coma developed. Two days after the malignant hyperthermic event, serum transaminase levels rose acutely to extremely high levels with concomitant elevations in bilirubin levels and a fall in prothrombin activity. Liver biopsy specimens in two patients showed marked perivenular necrosis and collapse. No specific treatment was directed at the phencyclidine intoxication. Two of the three patients survived. Submassive liver necrosis caused by malignant hyperthermia is an unusual complication of phencyclidine abuse.

  5. Phencyclidine increased while isolation rearing did not affect progressive ratio responding in rats: Investigating potential models of amotivation in schizophrenia.

    PubMed

    Amitai, Nurith; Powell, Susan B; Young, Jared W

    2017-11-22

    Schizophrenia is a debilitating neurodevelopmental disorder affecting 1% of the global population with heterogeneous symptoms including positive, negative, and cognitive. While treatment for positive symptoms exists, none have been developed to treat negative symptoms. Animal models of schizophrenia are required to test targeted treatments and since patients exhibit reduced effort (breakpoints) for reward in a progressive ratio (PR) task, we examined the PR breakpoints of rats treated with the NMDA receptor antagonist phencyclidine or those reared in isolation - two common manipulations used to induce schizophrenia-relevant behaviors in rodents. In two cohorts, the PR breakpoint for a palatable food reward was examined in Long Evans rats after: 1) a repeated phencyclidine regimen; 2) A subchronic phencyclidine regimen followed by drug washout; and 3) post-weaning social isolation. Rats treated with repeated phencyclidine and those following washout from phencyclidine exhibited higher PR breakpoints than vehicle-treated rats. The breakpoint of isolation reared rats did not differ from those socially reared, despite abnormalities of these rats in other schizophrenia-relevant behaviors. Despite their common use for modeling other schizophrenia-relevant behaviors neither phencyclidine treatment nor isolation rearing recreated the motivational deficits observed in patients with schizophrenia, as measured by PR breakpoint. Other manipulations, and negative symptom-relevant behaviors, require investigation prior to testing putative therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Myoglobinuric acute renal failure in phencyclidine overdose: report of observations in eight cases.

    PubMed

    Patel, R; Das, M; Palazzolo, M; Ansari, A; Balasubramaniam, S

    1980-11-01

    Eight cases of myoglobinuric acute renal failure that developed following exposure to phencyclidine were seen in the emergency department of the Martin Luther King Jr. General Hospital during a period of 36 months. All eight survived with complete recovery of renal function. Dialysis was necessary in three patients. Acute renal failure is an uncommon complication of phencyclidine abuse.

  7. Primate Phencyclidine Model of Schizophrenia: Sex-Specific Effects on Cognition, Brain Derived Neurotrophic Factor, Spine Synapses, and Dopamine Turnover in Prefrontal Cortex

    PubMed Central

    Groman, Stephanie M.; Jentsch, James D.; Leranth, Csaba; Redmond, D. Eugene; Kim, Jung D.; Diano, Sabrina; Roth, Robert H.

    2015-01-01

    Background: Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits. Methods: The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys. Results: One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance. Conclusions: As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia. PMID:25522392

  8. Identifying Drugs

    MedlinePlus

    ... Phencyclidine) Peyote and Mescaline Psilocybin Rohypnol Salvia Divinorum Spice/ K2, Synthetic Marijuana Steroids U-47700 Amphetamines Barbiturates ... Phencyclidine) Peyote and Mescaline Psilocybin Rohypnol Salvia Divinorum Spice/ K2, Synthetic Marijuana Steroids U-47700 Aerosol cans ...

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Therapeutic vaccines for substance dependence.

    PubMed

    Kosten, Thomas R; Biegel, Diane

    2002-10-01

    Several immunotherapies are under development for nicotine, cocaine and phencyclidine and a cocaine vaccine has started human trials. These therapies promise a new approach to diseases that have had limited treatment success and tremendous morbidity. Both the cocaine and nicotine addiction immunotherapies have reduced 'relapse' to drug use in animal model systems. To date, the active cocaine vaccine has few side effects and induces considerable antibody titers after active immunization in humans. Studies with the monoclonal phencyclidine immunotherapy provide intriguing evidence of sustained protection for months after single-dose administration. Other immunotherapy may include treatment of drug overdose, prevention of brain or cardiac toxicity and protection of a fetus during pregnancy in a drug abuser.

  20. 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.

  1. 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

  2. 76 FR 799 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-06

    ... Phencyclidine (7471) II Alphaprodine (9010) II Anileridine (9020) II Cocaine (9041) II Codeine (9050) II... effect on May 1, 1971. DEA has investigated United States Pharmacopeial Convention to ensure that the...

  3. 76 FR 25375 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-04

    ... Amphetamine (1100) II Phencyclidine (7471) II Cocaine (9041) II Diprenorphine (9058) II Fentanyl (9801) II The... States obligations under international treaties, conventions, or protocols in effect on May 1, 1971. DEA...

  4. 75 FR 14187 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-24

    ...)... I Amphetamine (1100) II Phencyclidine (7471) II Cocaine (9041) II Diprenorphine (9058) II Fentanyl... obligations under international treaties, conventions, or protocols in effect on May 1, 1971, at this time...

  5. 77 FR 70186 - Importer Of Controlled Substances; Notice Of Registration; Cerilliant Corporation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-23

    ... Secobarbital (2315) II Phencyclidine (7471) II Phenylacetone (8501) II Cocaine (9041) II Codeine (9050) II... with United States obligations under international treaties, conventions, or protocols in effect on May...

  6. 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.

  7. 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.

  8. 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- ...

  9. 76 FR 62448 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-07

    ... (2315) II Phencyclidine (7471) II Phenylacetone (8501) II Cocaine (9041) II Codeine (9050) II..., or protocols in effect on May 1, 1971. DEA has investigated Lipomed, Inc. to ensure that the company...

  10. 75 FR 36693 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-28

    ... Nabilone (7379) II Phencyclidine (7471) II Cocaine (9041) II Codeine (9050) II Diprenorphine (9058) II..., conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated Sigma Aldrich...

  11. 76 FR 23626 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-27

    ...) II Nabilone (7379) II Phencyclidine (7471) II Cocaine (9041) II Codeine (9050) II Diprenorphine (9058..., conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated Sigma Aldrich...

  12. 75 FR 75497 - Importer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-03

    ... (2315) II Phencyclidine (7471) II Phenylacetone (8501) II Cocaine (9041) II Codeine (9050) II..., or protocols in effect on May 1, 1971. DEA has investigated Lipomed, Inc. to ensure that the company...

  13. 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.

  14. 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

  15. 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

  16. 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...

  17. 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...

  18. 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.

  19. 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...

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

    PubMed

    Jentsch, J D; Roth, R H

    1999-03-01

    Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.

  6. 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

  7. 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...

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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)

  17. 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…

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus

    PubMed Central

    Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B.; Remmers, Christine; Xu, Jian; Meltzer, Herbert; Contractor, Anis

    2015-01-01

    Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. PMID:25937215

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. Effects of prenatal and perinatal administration of phencyclidine on the behavioral development of rat offspring.

    PubMed

    Nabeshima, T; Yamaguchi, K; Hiramatsu, M; Ishikawa, K; Furukawa, H; Kameyama, T

    1987-11-01

    The effects of prenatal and perinatal administration of a nonteratogenic dose of phencyclidine (PCP) on the behavioral development of Sprague-Dawley rats were examined. In the offspring prenatally treated with PCP (10 mg/kg) between days 7 and 17 of gestation, a decrease in maternal body weight in the gestation period, a decrease in fetal body weight and body length, a decrease in viability of offsprings, and a decrease in the body weights of the offspring in the nursing period were observed. Furthermore, PCP pups had difficulty performing the rota-rod task at 4 weeks and exhibited a decrease in sensitivity to challenged PCP at 5 weeks (female). In the offspring prenatally treated with PCP between days 7 and 21 of gestation, a decrease in the body weights of dams, fetuses and offspring, and a decrease in the viability of offsprings were observed. PCP pups showed an increase in the score for head-twitch response (male), a delay in the development of ambulation, negative geotaxis (male), bar holding and rope-descending behavior (female). However, the PCP administration during prenatal (between days 17 and 21 of gestation) and nursing periods showed only a decrease in viability and body weight of offspring, and a delay in the development of the separation of eyelids. These results suggest that more attention should be given to the developmental toxicity of PCP.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.

    PubMed

    Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B; Remmers, Christine L; Xu, Jian; Meltzer, Herbert Y; Contractor, Anis

    2016-01-01

    Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. 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

  9. 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.

  10. 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

  11. Phencyclidine administration during neurodevelopment alters network activity in prefrontal cortex and hippocampus in adult rats.

    PubMed

    Kjaerby, Celia; Hovelsø, Nanna; Dalby, Nils Ole; Sotty, Florence

    2017-08-01

    Symptoms of schizophrenia have been linked to insults during neurodevelopment such as NMDA receptor (NMDAR) antagonist exposure. In animal models, this leads to schizophrenia-like behavioral symptoms as well as molecular and functional changes within hippocampal and prefrontal regions. The aim of this study was to determine how administration of the NMDAR antagonist phencyclidine (PCP) during neurodevelopment affects functional network activity within the hippocampus and medial prefrontal cortex (mPFC). We recorded field potentials in vivo after electrical brain stem stimulation and observed a suppression of evoked theta power in ventral hippocampus, while evoked gamma power in mPFC was enhanced in rats administered with PCP neonatally. In addition, increased gamma synchrony elicited by acute administration of the NMDAR antagonist MK-801 was exaggerated in neonatal PCP animals. These data suggest that NMDAR antagonist exposure during brain development alters functional networks within hippocampus and mPFC possibly contributing to the reported behavioral symptoms of this animal model of schizophrenia. NEW & NOTEWORTHY We show that insults with a NMDA receptor antagonist during neurodevelopment lead to suppressed evoked theta oscillations in ventral hippocampus in adult rats, while evoked gamma oscillations are enhanced and hypersensitive to an acute challenge with a NMDA receptor antagonist in prefrontal cortex. These observations reveal the significance of neurodevelopmental disturbances in the evolvement of schizophrenia-like symptoms and contribute to the understanding of the functional deficits underlying aberrant behavior in this disease. Copyright © 2017 the American Physiological Society.

  12. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function.

    PubMed

    Gao, Jun; Qin, Rongyin; Li, Ming

    2015-04-01

    The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. © The Author(s) 2014.

  13. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function

    PubMed Central

    Gao, Jun; Qin, Rongyin; Li, Ming

    2016-01-01

    The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. PMID:25586399

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine.

    PubMed

    Matsuura, Akiko; Fujita, Yuko; Iyo, Masaomi; Hashimoto, Kenji

    2015-06-01

    A recent clinical study demonstrated that sodium benzoate (SB), a prototype competitive d-amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia. The objective of the study was to examine the effects of SB on behavioural abnormalities such as pre-pulse inhibition (PPI) deficits and hyperlocomotion in mice after a single administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP). The effects of SB on behavioural abnormalities (PPI deficits and hyperlocomotion) in mice after PCP administration were examined. Furthermore, effects of SB on tissue levels of amino acids were also examined. A single oral dose of SB (100, 300, or 1000 mg/kg) attenuated PPI deficits in mice after administration of PCP (3.0 mg/kg, s.c.) in a dose-dependent manner. In contrast, L-701,324 (10 mg/kg), an antagonist at the glycine site of the NMDA receptor, did not affect the effect of SB (1000 mg/kg) on PCP-induced PPI deficits. Furthermore, a single oral dose of SB (1000 mg/kg) significantly attenuated the hyperlocomotion in mice after administration of PCP (3.0 mg/kg, s.c.). However, a single oral dose of SB (1000 mg/kg) caused no changes to D-serine levels in plasma or in the frontal cortex, hippocampus, and striatum of these animals. This study suggests that SB induced antipsychotic effects in the PCP model of schizophrenia, although it did not increase D-serine levels in the brain.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1.

    PubMed

    Radonjić, Nevena V; Jakovcevski, Igor; Bumbaširević, Vladimir; Petronijević, Nataša D

    2013-06-01

    Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats.

    PubMed

    Schnakenberg Martin, Ashley M; OʼDonnell, Brian F; Millward, James B; Vohs, Jenifer L; Leishman, Emma; Bolbecker, Amanda R; Rass, Olga; Morzorati, Sandra L

    2017-01-01

    The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders. © 2017 S. Karger AG, Basel.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. Phencyclidine Disrupts the Auditory Steady State Response in Rats

    PubMed Central

    Leishman, Emma; O’Donnell, Brian F.; Millward, James B.; Vohs, Jenifer L.; Rass, Olga; Krishnan, Giri P.; Bolbecker, Amanda R.; Morzorati, Sandra L.

    2015-01-01

    The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule. PMID:26258486

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. The variability of ecstasy tablets composition in Brazil.

    PubMed

    Togni, Loraine R; Lanaro, Rafael; Resende, Rodrigo R; Costa, Jose L

    2015-01-01

    The content of ecstasy tablets has been changing over the years, and nowadays 3,4-methylenedioxymethamphetamine (MDMA) is not always present in the tablets. The aim of this study was to investigate the chemical composition in the seized tablets labeled as ecstasy. We analyzed samples from 150 different seizures made by Sao Paulo's State Police by gas chromatography-mass spectrometry. MDMA was present in 44.7% of the analyzed samples, and another twenty different active substances were identified in these tablets, such as caffeine, 2C-B, piperazines, amphetamines, phencyclidine, and others. Methamphetamine was present in 22% of these samples. The results demonstrate a huge shift in the pattern of trafficking of synthetic drugs, where MDMA has been replaced in tablets mostly by illicit psychoactive substances, in a clear attempt to bypass the law. The great variability in the tablets composition may lead to an increased risk of drug poisoning. © 2014 American Academy of Forensic Sciences.

  20. Addictive drugs and brain stimulation reward.

    PubMed

    Wise, R A

    1996-01-01

    Direct electrical or chemical stimulation of specific brain regions can establish response habits similar to those established by natural rewards such as food or sexual contact. Cocaine, mu and delta opiates, nicotine, phencyclidine, and cannabis each have actions that summate with rewarding electrical stimulation of the medial forebrain bundle (MFB). The reward-potentiating effects of amphetamine and opiates are associated with central sites of action where these drugs also have their direct rewarding effects, suggesting common mechanisms for drug reward per se and for drug potentiation of brain stimulation reward. The central sites at which these and perhaps other drugs of abuse potentiate brain stimulation reward and are rewarding in their own right are consistent with the hypothesis that the laboratory reward of brain stimulation and the pharmacological rewards of addictive drugs are habit forming because they act in the brain circuits that subserve more natural and biologically significant rewards.

  1. Nephrotoxic effects of designer drugs: synthetic is not better!

    PubMed

    Luciano, Randy L; Perazella, Mark A

    2014-06-01

    Designer drugs are synthetic, psychoactive substances with similar structures and activity to existing scheduled drugs or controlled chemical compounds. The use of these drugs is not generally considered illegal and they cannot be detected using standard toxicology tests--essentially they are considered to be 'legal highs'. Over the past several years, increasing numbers of designer drugs have become available. These drugs are classified as amphetamine derivatives, phenylpiperazine derivatives, synthetic cathinones, synthetic cannabinoids, phencyclidine derivatives and synthetic opioids. Although euphoria is the desired effect, neuropsychiatric and cardiac manifestations are frequently observed in individuals using these drugs at high doses or using drugs that are contaminated with other substances. Some designer drugs are also associated with adverse renal effects, including acute kidney injury from pigment nephropathy, acute tubular necrosis, obstructive nephropathy and hyponatraemia. The misuse of these drugs should be recognized and clinicians made aware of the potential for acute nephrotoxicity as the health burden of these compounds increases.

  2. From the street to the laboratory: analytical profiles of methoxetamine, 3-methoxyeticyclidine and 3-methoxyphencyclidine and their determination in three biological matrices.

    PubMed

    De Paoli, Giorgia; Brandt, Simon D; Wallach, Jason; Archer, Roland P; Pounder, Derrick J

    2013-06-01

    Three psychoactive arylcyclohexylamines, advertised as "research chemicals," were obtained from an online retailer and characterized by gas chromatography ion trap electron and chemical ionization mass spectrometry, nuclear magnetic resonance spectroscopy and diode array detection. The three phencyclidines were identified as 2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone (methoxetamine), N-ethyl-1-(3-methoxyphenyl)cyclohexanamine and 1-[1-(3-methoxyphenyl)cyclohexyl]piperidine. A qualitative/quantitative method of analysis was developed and validated using liquid chromatography (HPLC) electrospray tandem mass spectrometry and ultraviolet (UV) detection for the determination of these compounds in blood, urine and vitreous humor. HPLC-UV proved to be a robust, accurate and precise method for the qualitative and quantitative analysis of these substances in biological fluids (0.16-5.0 mg/L), whereas the mass spectrometer was useful as a confirmatory tool.

  3. Glutamate in schizophrenia: clinical and research implications.

    PubMed

    Goff, D C; Wine, L

    1997-10-30

    The excitatory amino acids, glutamate and aspartate, are of interest to schizophrenia research because of their roles in neurodevelopment, neurotoxicity and neurotransmission. Recent evidence suggests that densities of glutamatergic receptors and the ratios of subunits composing these receptors may be altered in schizophrenia, although it is unclear whether these changes are primary or compensatory. Agents acting at the phencyclidine binding site of the NMDA receptor produce symptoms of schizophrenia in normal subjects, and precipitate relapse in patients with schizophrenia. The improvement of negative symptoms with agents acting at the glycine modulatory site of the NMDA receptor, as well as preliminary evidence that clozapine may differ from conventional neuroleptic agents in its effects on glutamatergic systems, suggest that clinical implications may follow from this model. While geriatric patients may be at increased risk for glutamate-mediated neurotoxicity, very little is known about the specific relevance of this model to geriatric patients with schizophrenia.

  4. “Smoking Wet”

    PubMed Central

    Gilbert, Christopher R.; Baram, Michael; Cavarocchi, Nicholas C.

    2013-01-01

    Reports have suggested that the use of a dangerously tainted form of marijuana, referred to in the vernacular as “wet” or “fry,” has increased. Marijuana cigarettes are dipped into or laced with other substances, typically formaldehyde, phencyclidine, or both. Inhaling smoke from these cigarettes can cause lung injuries. We report the cases of 2 young adults who presented at our hospital with respiratory failure soon after they had smoked “wet” marijuana cigarettes. In both patients, progressive hypoxemic respiratory failure necessitated rescue therapy with extracorporeal membrane oxygenation. After lengthy hospitalizations, both patients recovered with only mild pulmonary function abnormalities. To our knowledge, this is the first 2-patient report of severe respiratory failure and rescue therapy with extracorporeal oxygenation after the smoking of marijuana cigarettes thus tainted. We believe that, in young adults with an unexplained presentation of severe respiratory failure, the possibility of exposure to tainted marijuana cigarettes should be considered. PMID:23466531

  5. Drugs of abuse that cause developing neurons to commit suicide.

    PubMed

    Farber, Nuri B; Olney, John W

    2003-12-30

    When neuronal activity is abnormally suppressed during the developmental period of synaptogenesis, the timing and sequence of synaptic connections is disrupted, and this causes nerve cells to receive an internal signal to commit suicide, a form of cell death known as "apoptosis". By altering glutamate and GABA transmission alcohol suppresses neuronal activity, causing millions of nerve cells to commit suicide in the developing brain. This proapoptotic effect of alcohol provides a likely explanation for the diminished brain size and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome. These findings have public health significance, not only in relation to fetal alcohol syndrome, but also in relation to several other drugs of abuse and various drugs used in obstetric and pediatric medicine, because these additional drugs (e.g. phencyclidine, ketamine, benzodiazepines, barbiturates) also suppress neuronal activity and drive developing neurons to commit suicide.

  6. The role of physicians as medical review officers in workplace drug testing programs. In pursuit of the last nanogram.

    PubMed Central

    Clark, H W

    1990-01-01

    In discussing the role of physicians in workplace drug testing programs, I focus on the recent Department of Transportation regulations that require drug testing in such regulated industries as interstate trucking, air transportation, mass transit, and the railroads. These regulations require that applicable drug testing programs employ physicians as medical review officers to evaluate positive tests that have been screened and confirmed by different techniques to determine if there is a legal medical explanation for the result. The drug testing program tests for the presence of amphetamine, cocaine, tetrahydrocannabinol, opiates, and phencyclidine. If an employee testing positive has an acceptable medical explanation, the result is to be reported as negative. Little practical advice exists for medical review officers, and they must be aware of key elements of the regulations and potential trouble spots. PMID:2190419

  7. 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

  8. 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.

  9. 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).

  10. Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

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

    Keana, J.F.W.; McBurney, R.N.; Scherz, M.W.

    1989-07-01

    Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, {sup 3}H-labeled 1-(1-(2-thienyl)cyclohexyl)piperidine and (+)-({sup 3}H)MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These dairylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. The results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the developmentmore » of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack.« less

  11. Quantitative determination of 43 common drugs and drugs of abuse in human serum by HPLC-MS/MS.

    PubMed

    Bassan, David M; Erdmann, Freidoon; Krüll, Ralf

    2011-04-01

    An analytical procedure for the simultaneous determination in human serum of 43 common drugs of abuse and their metabolites belonging to the different chemical and toxicological classes of amphetamines, benzodiazepines, dibenzazepines, cocaine, lysergic acid diethylamide, opioids, phencyclidine, tricyclic antidepressants, and zolpidem, using 33 deuterated standards, is presented. The sample treatment was developed to be a very simple protein precipitation and filtration. All analyses were performed with a high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry in positive ionization mode. All analytes were calibrated up to 550 μg/L. The limit of detection ranged from 0.6 ng/mL (EDDP) to 13.7 ng/mL (flunitrazepam). The method has been validated according to the guidelines of the Gesellschaft für Toxikologische und Forensische Chemie, using three multiple reaction mode (MRM) transitions and retention time for positive compound identification, instead of two MRMs, in anticipation of the new guidelines for January 2011.

  12. Membrane Inlet Mass Spectrometry for Homeland Security and Forensic Applications

    NASA Astrophysics Data System (ADS)

    Giannoukos, Stamatios; Brkić, Boris; Taylor, Stephen; France, Neil

    2015-02-01

    A man-portable membrane inlet mass spectrometer has been built and tested to detect and monitor characteristic odors emitted from the human body and also from threat substances. In each case, a heated membrane sampling probe was used. During human scent monitoring experiments, data were obtained for inorganic gases and volatile organic compounds emitted from human breath and sweat in a confined space. Volatile emissions were detected from the human body at low ppb concentrations. Experiments with compounds associated with narcotics, explosives, and chemical warfare agents were conducted for a range of membrane types. Test compounds included methyl benzoate (odor signature of cocaine), piperidine (precursor in clandestine phencyclidine manufacturing processes), 2-nitrotoluene (breakdown product of TNT), cyclohexanone (volatile signature of plastic explosives), dimethyl methylphosphonate (used in sarin and soman nerve agent production), and 2-chloroethyl ethyl sulfide (simulant compound for sulfur mustard gas). Gas phase calibration experiments were performed allowing sub-ppb LOD to be established. The results showed excellent linearity versus concentration and rapid membrane response times.

  13. 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

  14. Membrane inlet mass spectrometry for homeland security and forensic applications.

    PubMed

    Giannoukos, Stamatios; Brkić, Boris; Taylor, Stephen; France, Neil

    2015-02-01

    A man-portable membrane inlet mass spectrometer has been built and tested to detect and monitor characteristic odors emitted from the human body and also from threat substances. In each case, a heated membrane sampling probe was used. During human scent monitoring experiments, data were obtained for inorganic gases and volatile organic compounds emitted from human breath and sweat in a confined space. Volatile emissions were detected from the human body at low ppb concentrations. Experiments with compounds associated with narcotics, explosives, and chemical warfare agents were conducted for a range of membrane types. Test compounds included methyl benzoate (odor signature of cocaine), piperidine (precursor in clandestine phencyclidine manufacturing processes), 2-nitrotoluene (breakdown product of TNT), cyclohexanone (volatile signature of plastic explosives), dimethyl methylphosphonate (used in sarin and soman nerve agent production), and 2-chloroethyl ethyl sulfide (simulant compound for sulfur mustard gas). Gas phase calibration experiments were performed allowing sub-ppb LOD to be established. The results showed excellent linearity versus concentration and rapid membrane response times.

  15. Paliperidone for the treatment of ketamine-induced psychosis: a case report.

    PubMed

    Zuccoli, M L; Muscella, A; Fucile, C; Carrozzino, R; Mattioli, F; Martelli, A; Orengo, S

    2014-01-01

    Ketamine is an anaesthetic and analgesic drug synthesized in the 1960s from phencyclidine. The recreational use of ketamine increased among the dance culture of techno and house music, in particular in clubs, discotheques, and rave parties. The psychotropic effects of ketamine are now well known and they range from dissociation to positive, negative, and cognitive schizophrenia-like symptoms. We report a case of a chronic oral consumption of ketamine which induced agitation, behavioral abnormalities, and loss of contact with reality in a poly-drug abuser; these symptoms persisted more than two weeks after the drug consumption had stopped. Antipsychotic treatment with paliperidone led to a successful management of the psychosis, getting a complete resolution of the clinical picture. Paliperidone has proven to be very effective in the treatment of ketamine-induced disorders. Moreover, the pharmacological action and metabolism of paliperidone are poorly dependent from the activity of liver enzymes, so that it seems to be one of the best second generation antipsychotics for the treatment of smokers and alcohol abusers.

  16. Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard

    PubMed Central

    Esse, Katherine; Fossati-Bellani, Marco; Traylor, Angela; Martin-Schild, Sheryl

    2011-01-01

    Drug abuse robs individuals of their jobs, their families, and their free will as they succumb to addiction; but may cost even more: a life of disability or even life lost due to stroke. Many illicit drugs have been linked to major cardiovascular events and other comorbidities, including cocaine, amphetamines, ecstasy, heroin, phencyclidine, lysergic acid diethylamide, and marijuana. This review focuses on available epidemiological data, mechanisms of action, particularly those leading to cerebrovascular events, and it is based on papers published in English in PubMed during 1950 through February 2011. Each drug's unique interactions with the brain and vasculature predispose even young, healthy people to ischemic or hemorrhagic stroke. Cocaine and amphetamines have the strongest association with stroke. However, the level of evidence firmly linking other drugs to stroke pathogenesis is weak. Large epidemiological studies and systematic evaluation of each drug's action on the brain and cardiovascular system are needed to reveal the full impact of drug use on the population. PMID:22398980

  17. Military chemical warfare agent human subjects testing: part 2--long-term health effects among participants of U.S. military chemical warfare agent testing.

    PubMed

    Brown, Mark

    2009-10-01

    Military chemical warfare agent testing from World War I to 1975 produced thousands of veterans with concerns about how their participation affected their health. A companion article describes the history of these experiments, and how the lack of clinical data hampers evaluation of long-term health consequences. Conversely, much information is available about specific agents tested and their long-term health effects in other populations, which may be invaluable for helping clinicians respond effectively to the health care and other needs of affected veterans. The following review describes tested agents and their known long-term health consequences. Although hundreds of chemicals were tested, they fall into only about a half-dozen pharmaceutical classes, including common pharmaceuticals; anticholinesterase agents including military nerve agents and pesticides; anticholinergic glycolic acid esters such as atropine; acetylcholine reactivators such as 2-PAM; psychoactive compounds including cannabinoids, phencyclidine, and LSD; and irritants including tear gas and riot control agents.

  18. Bridged bicyclic systems as acetylcholinesterase reactivators and pretreatment drugs. Annual report, 15 July 1988-14 July 1989

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

    Moriarty, R.M.

    1990-03-30

    During the past year a large number substituted carbamates, thiocarbamates of various bridged aza bicyclic oximes and their methiodides and meth chlorides have been synthesized. Among these are: (i) O-(N-Substituted carbamoyl)-3-tropinone oxime methiodides and methchlorides, (ii) 0-(N-Substituted carbamoyl)-6-cyano trop-3-ene-2-one oxime methiodides, (iii) O-N-(2`,3`,4`, 6`-Tetra-0-acetyl- b-D-glucopyranosyl thiocarbamoyl)-3-tropinone oxime and its methiodide. Synthesis of 1,6-bis-N`,N`-dimethyl- 3`-oximino-0-carbamoyl tropanonium-N-y1 hexane diiodide and 2,5- bis-(N`N`-dimethyl- 3`-oximino-0-carbamoyl tropanonium-N-yl)-toluene diiodide have been achieved. From phencyclidine a series 4-phenyl-4-0-(N-substituted carbamoyl)-4`-piperidone oxime-1`-yl-1-methyl piperidone methiodides have been synthesized. Syntheses of 0-(N-substituted carbamoyl)-3-exo-dimethyl aminomethyl2-norbornone oximes and their methiodides have been accomplished.

  19. Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard.

    PubMed

    Esse, Katherine; Fossati-Bellani, Marco; Traylor, Angela; Martin-Schild, Sheryl

    2011-09-01

    Drug abuse robs individuals of their jobs, their families, and their free will as they succumb to addiction; but may cost even more: a life of disability or even life lost due to stroke. Many illicit drugs have been linked to major cardiovascular events and other comorbidities, including cocaine, amphetamines, ecstasy, heroin, phencyclidine, lysergic acid diethylamide, and marijuana. This review focuses on available epidemiological data, mechanisms of action, particularly those leading to cerebrovascular events, and it is based on papers published in English in PubMed during 1950 through February 2011. Each drug's unique interactions with the brain and vasculature predispose even young, healthy people to ischemic or hemorrhagic stroke. Cocaine and amphetamines have the strongest association with stroke. However, the level of evidence firmly linking other drugs to stroke pathogenesis is weak. Large epidemiological studies and systematic evaluation of each drug's action on the brain and cardiovascular system are needed to reveal the full impact of drug use on the population.

  20. Dextromethorphan abuse leading to assault, suicide, or homicide.

    PubMed

    Logan, Barry K; Yeakel, Jillian K; Goldfogel, Gary; Frost, Michael P; Sandstrom, Greg; Wickham, Dennis J

    2012-09-01

    Dextromethorphan is a commonly encountered antitussive medication which has found additional therapeutic use in the treatment of pseudobulbar disorder and as an adjunct to opiate use in pain management. Dextromethorphan at high doses has phencyclidine-like effects on the NMDA receptor system; recreational use of high doses has been found to cause mania and hallucinations. The toxicology and pharmacology of the drug in abuse are reviewed, and the historical literature of adverse psychiatric outcomes is assessed. Five new cases of dextromethorphan intoxication that resulted in assault, suicide, and homicide are reported, together with the corresponding toxicology results. Blood concentrations ranged from 300 to 19,000 μg/L. These results are compared with typical concentrations reported in therapeutic use and impaired driving cases. Based on these findings, dextromethorphan should be considered as a potential causative agent in subjects presenting with mania, psychosis, or hallucinations, and abusers are at risk for violent and self-destructive acts. © 2012 American Academy of Forensic Sciences.

  1. New psychoactive substances: an overview on recent publications on their toxicodynamics and toxicokinetics.

    PubMed

    Meyer, Markus R

    2016-10-01

    This review article covers English-written and PubMed-listed review articles and original studies published between January 2015 and April 2016 dealing with the toxicodynamics and toxicokinetics of new psychoactive substances. Compounds covered include stimulants and entactogens, synthetic cannabinoids, tryptamines, NBOMes, phencyclidine-like drugs, benzodiazepines, and opioids. First, an overview and discussion is provided on timely review articles followed by an overview and discussion on recent original studies. Both sections are then concluded by an opinion on these latest developments. This review shows that the NPS market is still highly dynamic and that the data published on their toxicodynamics and toxicokinetics can hardly keep pace with the appearance of new entities. However, data available are very helpful to understand and predict how NPS may behave in severe intoxication. The currently best-documented parameter is the in vitro metabolism of NPS, a prerequisite to allow detection of NPS in biological matrices in cases of acute intoxications or chronic consumption. However, additional data such as their chronic toxicity are still lacking.

  2. Ketamine-Based Anesthetic Protocols and Evoked Potential Monitoring: A Risk/Benefit Overview.

    PubMed

    Stoicea, Nicoleta; Versteeg, Gregory; Florescu, Diana; Joseph, Nicholas; Fiorda-Diaz, Juan; Navarrete, Víctor; Bergese, Sergio D

    2016-01-01

    Since its discovery, ketamine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist related to phencyclidine, has been linked to multiple adverse reactions sometimes described as "out of body" and "near death experiences," including emergence phenomena, delusions, hallucinations, delirium, and confusion. Due to these effects, ketamine has been withdrawn from mainstream anesthetic use in adult patients. Evoked potentials (EPs) are utilized to monitor neural pathways during surgery, detect intraoperative stress or damage, detect and define the level of neural lesions, and define abnormalities. Unfortunately, many of the volatile anesthetics commonly used during spinal and neurologic procedures suppress EP amplitude and monitoring. Ketamine has been found in several preclinical and clinical studies to actually increase EP amplitude and thus has been used as an analgesic adjunct in procedures where EP monitoring is critical. Once the gap in our knowledge of ketamine's risks has been sufficiently addressed in animal models, informed clinical trials should be conducted in order to properly incorporate ketamine-based anesthetic regimens during EP-monitored neurosurgeries.

  3. Fitness for duty in the nuclear power industry: A review of technical issues

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

    Moore, C.; Barnes, V.; Hauth, J.

    This report presents information gathered and analyzed in support of the US Nuclear Regulatory Commission's (NRC's) efforts to develop a rule that will ensure that workers with unescorted access to protected areas of nuclear power plants are fit for duty. This report supplements information previously published in NUREG/CR-5227, Fitness for Duty in the Nuclear Power Industry: A Review of Technical Issues (Barnes et al., 1988). The primary potential fitness-for-duty concern addressed in both of these reports is impairment caused by substance abuse, although other fitness concerns are discussed. This report addresses issues pertaining to workers' use and misuse of alcohol,more » prescription drugs, and over-the-counter drugs as fitness-for-duty concerns; responds to several questions raised by NRC Commissioners; discusses subversion of the chemical testing process and methods of preventing such subversion; and examines concerns about the urinalysis cutoff levels used when testing for marijuana metabolites, amphetamines, and phencyclidine (PCP).« less

  4. Adaptations of the Saker-Solomons test: simple, reliable colorimetric field assays for chloroquine and its metabolites in urine.

    PubMed

    Mount, D L; Nahlen, B L; Patchen, L C; Churchill, F C

    1989-01-01

    Two field-adapted colorimetric methods for measuring the antimalarial drug chloroquine in urine are described. Both are modifications of the method of Saker and Solomons for screening urine for phencyclidine and other drugs of abuse, using the colour reagent tetrabromophenolphthalein ethyl ester. One method is semiquantitative, detecting the presence of chloroquine (Cq) and its metabolites in urine with a 1 microgram/ml detection limit; it is more sensitive and reliable than the commonly used Dill-Glazko method and is as easy to apply in the field. The second method uses a hand-held, battery-operated filter photometer to quantify Cq and its metabolites with a 2 microgram/ml detection limit and a linear range up to 8 micrograms/ml. The first method was validated in the field using a published quantitative colorimetric method and samples from a malaria study in Nigeria. The second method was validated in the laboratory against high-performance liquid chromatographic results on paired samples from the Nigerian study. Both methods may be used in remote locations where malaria is endemic and no electricity is available.

  5. 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

  6. Ketamine-Based Anesthetic Protocols and Evoked Potential Monitoring: A Risk/Benefit Overview

    PubMed Central

    Stoicea, Nicoleta; Versteeg, Gregory; Florescu, Diana; Joseph, Nicholas; Fiorda-Diaz, Juan; Navarrete, Víctor; Bergese, Sergio D.

    2016-01-01

    Since its discovery, ketamine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist related to phencyclidine, has been linked to multiple adverse reactions sometimes described as “out of body” and “near death experiences,” including emergence phenomena, delusions, hallucinations, delirium, and confusion. Due to these effects, ketamine has been withdrawn from mainstream anesthetic use in adult patients. Evoked potentials (EPs) are utilized to monitor neural pathways during surgery, detect intraoperative stress or damage, detect and define the level of neural lesions, and define abnormalities. Unfortunately, many of the volatile anesthetics commonly used during spinal and neurologic procedures suppress EP amplitude and monitoring. Ketamine has been found in several preclinical and clinical studies to actually increase EP amplitude and thus has been used as an analgesic adjunct in procedures where EP monitoring is critical. Once the gap in our knowledge of ketamine's risks has been sufficiently addressed in animal models, informed clinical trials should be conducted in order to properly incorporate ketamine-based anesthetic regimens during EP-monitored neurosurgeries. PMID:26909017

  7. Psychosis: Atypical Limbic Epilepsy versus Limbic Hyperexcitability with Onset at Puberty?

    PubMed Central

    Sharp, Frank R.; Hendren, Robert L.

    2009-01-01

    Phencyclidine (PCP), Ketamine (Special K) and MK-801 are non-competitive NMDA antagonists that produce acute psychosis in humans. The psychosis produced by these psychomimetic drugs is indistinguishable from schizophrenia and includes both positive and negative symptoms. This drug-induced psychosis occurs after puberty in humans. This brief review argues that this psychosis is an atypical form of limbic epilepsy based upon MK-801 induced spike-and-wave activity in rats and based upon increased blood flow and metabolism in brain of patients with psychosis caused by these psychomimetics. Moreover, there is a specific limbic thalamcortical psychosis circuit that mediates cell injury in limbic cortex of rodents and may mediate this PCP-induced psychosis in humans. It is proposed that this thalamocortical psychosis circuit develops at puberty and can mediate psychosis at puberty and in adulthood by PCP and ketamine-induced psychosis, and possibly in schizophrenia, bipolar disease and other psychotic states. Finally, based upon this developmentally regulated psychosis-epilepsy related thalamocortical circuitry, it is proposed that anti-epileptic drugs that promote GABAergic mechanisms might decrease the probability of episodic psychosis from any cause. PMID:17416210

  8. Unconventional ligands and modulators of nicotinic receptors.

    PubMed

    Pereira, Edna F R; Hilmas, Corey; Santos, Mariton D; Alkondon, Manickavasagom; Maelicke, Alfred; Albuquerque, Edson X

    2002-12-01

    Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and beta-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered. Copyright 2002 Wiley Periodicals, Inc.

  9. Drugs in hair. Part I. Metabolisms of major drug classes.

    PubMed

    White, R M

    2017-01-01

    Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered. Copyright © 2017 Central Police University.

  10. Surveillance of drug abuse in Hong Kong by hair analysis using LC-MS/MS.

    PubMed

    Leung, K Wing; Wong, Zack C F; Ho, Janet Y M; Yip, Ada W S; Cheung, Jerry K H; Ho, Karen K L; Duan, Ran; Tsim, Karl W K

    2018-06-01

    The aim of this study is to reveal the habits of drug abusers in hair samples from drug rehabilitation units in Hong Kong. With the application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, a total of 1771 hair samples were analyzed during the period of hair testing service (January 2012 to March 2016) provided to 14 drug rehabilitation units including non-governmental organizations (NGOs), rehabilitation centers, and medical clinics. Hair samples were analyzed for abused drugs and their metabolites simultaneously, including ketamine, norketamine, cocaine, benzoylecgonine, cocaethylene, norcocaine, codeine, MDMA, MDA, MDEA, amphetamine, methamphetamine, morphine, 6-acetylmorphine, phencyclidine, and methadone. The results showed that ketamine (77.2%), cocaine (21.3%), and methamphetamine (16.5%) were the frequently detected drugs among those drug abusers, which is consistent with the reported data. In addition, the usage of multiple drugs was also observed in the hair samples. About 29% of drug-positive samples were detected with multiple drug use. Our studies prove that our locally developed hair drug-testing method and service can be a valid tool to monitor the use of abused drugs, and which could facilitate rehabilitation program management. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.

    PubMed

    Chen, Xiao-Wen; Sun, Yuan-Yuan; Fu, Lei; Li, Jian-Qi

    2016-11-10

    A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Influence of chemical straightening on the stability of drugs of abuse in hair.

    PubMed

    Pritchett, Jeanita S; Phinney, Karen W

    2015-01-01

    Chemical straightening, also known as a relaxer, is ubiquitously used among African American women to obtain straighter hair compared with their natural tresses. This study focused on the stability of drugs of abuse in hair after a single application of the relaxer. Commercially available 'Lye' or 'No-Lye' chemical straightening products (Silk Elements™) were applied in vitro to drug-fortified hair (standard reference materials (SRM) 2379 and 2380) and hairs clipped from established drug users. Target analytes (cocaine (COC), benzoylecgonine (BZE), cocaethylene (CE), phencyclidine and tetrahydrocannabinol) were isolated using solid-phase extraction and then analyzed with isotope dilution gas chromatography-mass spectrometry with selective ion monitoring. After either treatment, drug concentrations were significantly (P < 0.05) decreased in both the SRM sample and the hair from authentic abusers. In the SRM groups, 6-67% of the original concentration remained after a single chemical treatment. Similarly, only 5-30% of the original concentration remained in authentic drug hairs that had formerly tested positive for COC, BZE and CE. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  13. [Immunotherapies for drug addictions].

    PubMed

    Montoya, Ivan

    2008-01-01

    Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders.

  14. A hybrid approach to urine drug testing using high-resolution mass spectrometry and select immunoassays.

    PubMed

    McMillin, Gwendolyn A; Marin, Stephanie J; Johnson-Davis, Kamisha L; Lawlor, Bryan G; Strathmann, Frederick G

    2015-02-01

    The major objective of this research was to propose a simplified approach for the evaluation of medication adherence in chronic pain management patients, using liquid chromatography time-of-flight (TOF) mass spectrometry, performed in parallel with select homogeneous enzyme immunoassays (HEIAs). We called it a "hybrid" approach to urine drug testing. The hybrid approach was defined based on anticipated positivity rates, availability of commercial reagents for HEIAs, and assay performance, particularly analytical sensitivity and specificity for drug(s) of interest. Subsequent to implementation of the hybrid approach, time to result was compared with that observed with other urine drug testing approaches. Opioids, benzodiazepines, zolpidem, amphetamine-like stimulants, and methylphenidate metabolite were detected by TOF mass spectrometry to maximize specificity and sensitivity of these 37 drug analytes. Barbiturates, cannabinoid metabolite, carisoprodol, cocaine metabolite, ethyl glucuronide, methadone, phencyclidine, propoxyphene, and tramadol were detected by HEIAs that performed adequately and/or for which positivity rates were very low. Time to result was significantly reduced compared with the traditional approach. The hybrid approach to urine drug testing provides a simplified and analytically specific testing process that minimizes the need for secondary confirmation. Copyright© by the American Society for Clinical Pathology.

  15. Inmunoterapias para las adicciones a las drogas Immunotherapies for Drug Addictions

    PubMed Central

    Montoya, Iván D.

    2008-01-01

    Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders. PMID:18551223

  16. Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

    PubMed Central

    Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

    2012-01-01

    N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896

  17. Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition

    PubMed Central

    2011-01-01

    Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. Results We present and justify a new technique for comparing pairs of networks--in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD), which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC) of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). This provides us with a means to quantify which predefined metabolic pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolite pathway database) were altered in the PFC of PCP-treated rats. Several significant changes were discovered, notably: 1) neuroactive ligands active at glutamate and GABA receptors are disrupted in the PFC of PCP-treated animals, 2) glutamate dysfunction in these animals was not limited to compromised glutamatergic neurotransmission but also involves the disruption of metabolic pathways linked to glutamate; and 3) a specific series of purine reactions Xanthine ← Hypoxyanthine ↔ Inosine ← IMP → adenylosuccinate is also disrupted in the PFC of PCP-treated animals. Conclusions Network reordering via the GSVD provides a means to discover statistically validated differences in clustering between a pair of networks. In practice this analytical approach, when applied to metabolomic data, allows us to quantify the alterations in metabolic pathways between two experimental groups. With this new computational technique we identified metabolic pathway alterations that are consistent with known results. Furthermore, we discovered disruption in a novel series of purine reactions that may contribute to the PFC dysfunction and cognitive deficits seen in schizophrenia. PMID:21575198

  18. [Ketamine--dreams and realities].

    PubMed

    Arditti, J; Spadari, M; de Haro, L; Brun, A; Bourdon, J H; Valli, M

    2002-01-01

    Ketamine is an anaesthetic used in human medicine and veterinary practice, synthesised on 1962 and marketed on 1970 in France. Recreational uses were described during 1992 in the medical community and in 1996 in the dance settings. The chemical name of ketamine is 2--(2chlorophenyl)2-(methylamine)-cyclohexanone, an aryl cyclohexylamine, structurally related to phencyclidine. Ketamine is known under the following street names: Keta K, Kate, Special K, Vitamin K, la Golden, la Vétérinaire. Ketamine is used intranasally, orally and intramusculary in recreational use. Ketamine is manufactured by the chemical industry. Due to the complicated synthesis, it is sold illicitly for recreational use. Ketamine is a dissociative drug, and the user enters in a psychedelic dream with hallucinations, floating sensation, feeling of dissociation of the mind from the body. The dream is forgotten, the user full in reality with loss of self control, risk of acute intoxication. In long-term exposure, tolerance, dependence, withdrawal signs and flash back are described. Ketamine trademarks are subject to control in France through medicine legislation Ketamine and its salts are subject to control under the national legislation on narcotics and psychotropics substance. From September 2001, the theft of medical and veterinary trademarks have to be declared to police, care health authority Pharmacy control authority and French Health Products Safety Agency.

  19. PCP and hallucinogens.

    PubMed

    Carroll, M E

    1990-01-01

    In this review phencyclidine and related arylcyclohexylamines and hallucinogens, using LSD as the prototype, are considered as two distinct classes of abused drugs. Within these classes drugs that are found on the street are discussed, and a current epidemiological summary is provided. The abuse liability and dependence potential of these drugs are evaluated by considering four major determinants of their abuse. First, is the ability of a drug to function as a positive reinforcer and increase the probability of operant behavior leading to its delivery. Animal data describing the reinforcing effects of PCP are reviewed with respect to the influence of variables controlling drug-reinforced behavior; however, there are no animal models of hallucinogen-reinforced behavior. Several methods of quantifying reinforcing efficacy are discussed. A second determinant is the subjective effects of the respective drugs. These effects are described and compared across drugs based on clinical reports in humans and drug discrimination studies in animals. A third determinant is the behavioral and physiological toxicity that results from acute and chronic use of these drugs. Clinical reports and results of sensitive tests that have been developed for laboratory animals are reviewed. A fourth determinant is the dependence potential that exists with these drugs, measured by tolerance development and the extent to which behavioral and physiological disturbances occur when drug use is terminated.

  20. Electroencephalographic, behavioral and receptor binding correlates of phencyclinoids in the rat

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

    Mattia, A.; Marquis, K.L.; Leccese, A.P.

    1988-08-01

    The pharmacology and structure-activity relationship of phencyclidine (PCP)-like drugs (phencyclinoids) were studied using electroencephalographic (EEG), behavioral and receptor binding techniques. The effects of PCP, 1-phenylcyclohexylamine HCl, N-methyl-1-phenycyclohexylamine HCl, N-ethyl-1-phenylcyclohexylamine HCl, N-(s-butyl)-1-phenylcyclohexylamine HCL, 1-(1-phenylcyclo-hexyl)-pyrrolidine HCl, 1-(1-(2-thienyl)cyclohexyl) piperidine HCl, 1-(1-(2-thienyl)cyclohexyl)-pyrrolidine HCl, ketamine and (+/-)-SKF 10047 were evaluated on the direct EEG and EEG spectra after acute i.v. injections (0.1-17.8 mg/kg). Similarities and differences were noted in the EEG dose-response curves. At lower doses of PCP and its analogs, low-amplitude theta waves predominated; however, at higher doses, high-amplitude, lower-frequency waves predominated. Qualitatively, the N-piperidine derivatives were similar to PCP and differed primarily inmore » potency. The benzomorphan (+/-)-SKF 10047 produced only theta activity at doses up to 12.8 mg/kg. These EEG effects occurred in conjunction with overt behaviors including locomotion, stereotypy and ataxia, concurrently assessed via observer-based rating scales. A strong correlation (r = 0.98) was obtained between the EEG and behavioral effects and the IC50 values from (/sup 3/H)PCP displacement experiments using crude rat brain homogenates.« less

  1. d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain.

    PubMed

    Cristino, Luigia; Luongo, Livio; Squillace, Marta; Paolone, Giovanna; Mango, Dalila; Piccinin, Sonia; Zianni, Elisa; Imperatore, Roberta; Iannotta, Monica; Longo, Francesco; Errico, Francesco; Vescovi, Angelo Luigi; Morari, Michele; Maione, Sabatino; Gardoni, Fabrizio; Nisticò, Robert; Usiello, Alessandro

    2015-05-01

    We have investigated the relevance of d-aspartate oxidase, the only enzyme known to selectively degrade d-aspartate (d-Asp), in modulating glutamatergic system homeostasis. Interestingly, the lack of the Ddo gene, by raising d-Asp content, induces a substantial increase in extracellular glutamate (Glu) levels in Ddo-mutant brains. Consistent with an exaggerated and persistent N-methyl-d-aspartate receptor (NMDAR) stimulation, we documented in Ddo knockouts severe age-dependent structural and functional alterations mirrored by expression of active caspases 3 and 7 along with appearance of dystrophic microglia and reactive astrocytes. In addition, prolonged elevation of d-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampal GluN1 and GluN2B subunits selectively located at synaptic sites and to increase in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-to-N-methyl-d-aspartate ratio. These effects, all of which converged on a progressive hyporesponsiveness at NMDAR sites, functionally resulted in a greater vulnerability to phencyclidine-induced prepulse inhibition deficits in mutants. In conclusion, our results indicate that d-aspartate oxidase, by strictly regulating d-Asp levels, impacts on the homeostasis of glutamatergic system, thus preventing accelerated neurodegenerative processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Are therapeutic vaccines an answer to the global problem of drug and alcohol abuse?

    PubMed

    Brashier, Dick B S; Sharma, Ashok Kumar; Akhoon, Neha

    2016-01-01

    Drug Abuse has become a major challenging problem for the society. It effects people of all countries economical strata's and all ages. According. Monetary loss all over the world regarding drug abuse is in million dollars, it not only has an impact on human productivity and healthcare cost but also on cost of crimes conducted by these drugs and alcohol abuse. Therapeutic vaccine has come as new approach to deal with this problem, after failures in search for a pharmaceutical agent to deal with drug of abuse and alcohol. Research in field of nicotine abuse has gone a way ahead with number of vaccines being tried clinically followed by cocaine, opioids, methamphetamine, phencyclidine and alcohol. All of them have a common mechanism of action by antibody production whereas alcohol acts by genetic intervention. None have being approved yet due to poor results in phase II trials, possibly due to not able to trigger an adequate immunological response. But still quest is on for cracking the ice by developing first successful vaccine against drug of abuse, that would follow for other drugs too. It would be great step in field of therapeutic vaccines for drug abuse after similar successful vaccines being approved for other diseases like cancer.

  3. Microfluidic chip based nano liquid chromatography coupled to tandem mass spectrometry for the determination of abused drugs and metabolites in human hair.

    PubMed

    Zhu, Kevin Y; Leung, K Wing; Ting, Annie K L; Wong, Zack C F; Ng, Winki Y Y; Choi, Roy C Y; Dong, Tina T X; Wang, Tiejie; Lau, David T W; Tsim, Karl W K

    2012-03-01

    A microfluidic chip based nano-HPLC coupled to tandem mass spectrometry (nano-HPLC-Chip-MS/MS) has been developed for simultaneous measurement of abused drugs and metabolites: cocaine, benzoylecgonine, cocaethylene, norcocaine, morphine, codeine, 6-acetylmorphine, phencyclidine, amphetamine, methamphetamine, MDMA, MDA, MDEA, and methadone in the hair of drug abusers. The microfluidic chip was fabricated by laminating polyimide films and it integrated an enrichment column, an analytical column and a nanospray tip. Drugs were extracted from hairs by sonication, and the chromatographic separation was achieved in 15 min. The drug identification and quantification criteria were fulfilled by the triple quardropule tandem mass spectrometry. The linear regression analysis was calibrated by deuterated internal standards with all of the R(2) at least over 0.993. The limit of detection (LOD) and the limit of quantification (LOQ) were from 0.1 to 0.75 and 0.2 to 1.25 pg/mg, respectively. The validation parameters including selectivity, accuracy, precision, stability, and matrix effect were also evaluated here. In conclusion, the developed sample preparation method coupled with the nano-HPLC-Chip-MS/MS method was able to reveal the presence of drugs in hairs from the drug abusers, with the enhanced sensitivity, compared with the conventional HPLC-MS/MS.

  4. 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.

  5. Nonnatural deaths among users of illicit drugs: pathological findings and illicit drug abuse stigmata.

    PubMed

    Delaveris, Gerd Jorunn Møller; Hoff-Olsen, Per; Rogde, Sidsel

    2015-03-01

    The aim of the study was to provide information on illicit drug abuse stigmata and general pathological findings among an adult narcotic drug-using population aged 20 to 59 years whose death was nonnatural. A total of 1603 medicolegal autopsy reports from 2000 to 2009 concerning cases positive for morphine, heroin, amphetamines, ecstasy, cannabis, LSD (lysergic acid diethylamide), PCP (phencyclidine), and high levels of GHB (γ-hydroxybutyric acid) in addition to methadone and buprenorphine were investigated. Reported findings of hepatitis, portal lymphadenopathy, recent injection marks, drug user's equipment, and numbers of significant pathological conditions were registered and analyzed according to cases positive for opiates, opioids (OPs), and central nervous system (CNS)-stimulating illicit drugs, respectively. Of the selected cases, 1305 were positive for one or more opiate or OP. Cases positive for OPs had significantly more findings of noninfectious pathological conditions. Hepatitis, portal lymphadenopathy, recent injections marks findings of drug user's equipment were all findings found more frequently among the opiate OP-positive individuals. Portal lymphadenopathy was significantly more often found in cases with hepatitis than in cases with other or no infection. In the population positive for CNS stimulants, hepatitis recent injection marks were more frequent findings than in the CNS stimulant-negative group, irrespective of whether they were opiate OP positive or negative.

  6. Use of “MGE Enhancers” for Labeling and Selection of Embryonic Stem Cell-Derived Medial Ganglionic Eminence (MGE) Progenitors and Neurons

    PubMed Central

    Chen, Ying-Jiun J.; Vogt, Daniel; Wang, Yanling; Visel, Axel; Silberberg, Shanni N.; Nicholas, Cory R.; Danjo, Teruko; Pollack, Joshua L.; Pennacchio, Len A.; Anderson, Stewart; Sasai, Yoshiki; Baraban, Scott C.; Kriegstein, Arnold R.; Alvarez-Buylla, Arturo; Rubenstein, John L. R.

    2013-01-01

    The medial ganglionic eminence (MGE) is an embryonic forebrain structure that generates the majority of cortical interneurons. MGE transplantation into specific regions of the postnatal central nervous system modifies circuit function and improves deficits in mouse models of epilepsy, Parkinson's disease, pain, and phencyclidine-induced cognitive deficits. Herein, we describe approaches to generate MGE-like progenitor cells from mouse embryonic stem (ES) cells. Using a modified embryoid body method, we provided gene expression evidence that mouse ES-derived Lhx6+ cells closely resemble immature interneurons generated from authentic MGE-derived Lhx6+ cells. We hypothesized that enhancers that are active in the mouse MGE would be useful tools in detecting when ES cells differentiate into MGE cells. Here we demonstrate the utility of enhancer elements [422 (DlxI12b), Lhx6, 692, 1056, and 1538] as tools to mark MGE-like cells in ES cell differentiation experiments. We found that enhancers DlxI12b, 692, and 1538 are active in Lhx6-GFP+ cells, while enhancer 1056 is active in Olig2+ cells. These data demonstrate unique techniques to follow and purify MGE-like derivatives from ES cells, including GABAergic cortical interneurons and oligodendrocytes, for use in stem cell-based therapeutic assays and treatments. PMID:23658702

  7. 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

  8. Impaired Limbic Cortico-Striatal Structure and Sustained Visual Attention in a Rodent Model of Schizophrenia

    PubMed Central

    Barnes, Samuel A.; Sawiak, Stephen J.; Caprioli, Daniele; Jupp, Bianca; Buonincontri, Guido; Mar, Adam C.; Harte, Michael K.; Fletcher, Paul C.; Robbins, Trevor W.; Neill, Jo C.

    2015-01-01

    Background: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia. Methods: Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. Results: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex. Conclusions: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function. PMID:25552430

  9. 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

  10. 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.

  11. Immunotherapy for the treatment of drug abuse.

    PubMed

    Kosten, Thomas; Owens, S Michael

    2005-10-01

    Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the brain, the rate of clearance across the blood-brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions.

  12. Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: A preliminary investigation.

    PubMed

    McLean, Samantha L; Harte, Michael K; Neill, Joanna C; Young, Andrew Mj

    2017-06-01

    Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase was observed. These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

  13. Comparative effects of phencyclidine (PCP) and. delta. /sup 9/-tetrahydrocannabinol (THC) on glucose oxidation in the rat testis

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

    Husain, S.; Bauer, V.

    Glucose and fructose are important fuels of cellular energetics in organs like testis and brain. The previous in-vitro studies indicated that THC may disrupt many gonadal functions by inhibiting energy metabolism in the testis. PCP is sold on the street as any one of a variety of psychoactive drugs. Most commonly it is misrepresented as THC. Therefore, to compare the effects of PCP and THC on glucose utilization, in-vitro radiorespirometric experiments were conducted in rat testicular tissues. The /sup 14/CO/sub 2/ production from 5.5 mM radiolabelled glucose was followed in the presence and absence of 0.2, 0.1, 0.05, 0.01, 0.005,more » 0.0025 mM PCP. PCP produced a dose-dependent biphasic effect, stimulating /sup 14/CO/sub 2/ production by 6.2, 17 and 5.8% and then inhibiting it by 13.2, 15.4 and 8.9% with respective concentrations of PCP. This is in contrast to THC which produced a dose-related inhibition of 15.2, 18.1, 20.1 and 25.3% in /sup 14/CO/sub 2/ production with 0.1, 0.2, 0.3 and 0.4 mM THC. These observations are significant due to the possible abuse of PCP together with THC either deliberately or by misrepresentation.« less

  14. 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

  15. Evaluation of Intraosseous Fluid as an Alternative Biological Specimen in Postmortem Toxicology.

    PubMed

    Rodda, Luke N; Volk, Justin A; Moffat, Ellen; Williams, Chinyere M; Lynch, Kara L; Wu, Alan H B

    2018-04-01

    The postmortem redistribution phenomenon is an important factor in the interpretation of blood drug concentrations as a cause or factor in death. Intraosseous fluid (IOF) may serve as an alternative matrix for drug testing. Intraosseous fluid was collected from the left and right tibias and humerus of 29 decedents using the Arrow EZ-IO Intraosseous Vascular Access System. Standard autopsy specimens including blood were also collected at the same time during autopsy. Blood and IOF specimens were screened by immunoassay for opioids, fentanyl analogs, oxycodone, methadone, cocaine, methamphetamine, amphetamines, phencyclidine, tricyclic antidepressants, benzodiazepines and cannabinoids, using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Correlation between cardiac/central blood ELISA and IOF ELISA results was mostly 100% for drug targets. Further blood confirmation analysis was performed by gas chromatography mass spectrometry also showed comparable correlation to IOF screen results. There was no significant difference between the IOF sites or sides of the body. This novel study supports the use of IOF as an alternative postmortem specimen for toxicological investigations as a potentially less-compromised tissue in decomposed or traumatized bodies. Preliminary data is provided for the screening of common drugs of abuse in IOF that may show to be subject to alternative rates of postmortem redistribution than to that of other biological specimens in future studies that quantitate IOF drug concentrations.

  16. Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons

    PubMed Central

    Zhong, Ping; Yan, Zhen

    2016-01-01

    Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions. PMID:25146372

  17. Central phencyclidine (PCP) receptor binding is glutamate dependent: evidence for a PCP/excitatory amino acid receptor (EAAR) complex

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

    Loo, P.; Braunwalder, A.; Lehmann, J.

    PCP and other dissociative anesthetica block the increase in neuronal firing rate evoked by the EAAR agonist, N-methyl-Daspartate. NMDA and other EAAs such as glutamate (glu) have not been previously shown to affect PCP ligand binding. In the present study, using once washed rat forebrain membranes, 10 ..mu..M-glu was found to increase the binding of (/sup 3/H)TCP, a PCP analog, to defined PCP recognition sites by 20%. Removal of glu and aspartate (asp) by extensive washing decreased TCP binding by 75-90%. In these membranes, 10 ..mu..M L-glu increased TCP binding 3-fold. This effect was stereospecific and evoked by other EAAsmore » with the order of activity, L-glu > D-asp > L- asp > NMDA > D-glu > quisqualate. Kainate, GABA, NE, DA, 5-HT, 2-chloroadenosine, oxotremorine and histamine had no effect on TCP binding at concentrations up to 100 ..mu..M. The effects of L-glu were attenuated by the NMDA-type receptor antagonist, 2-amino-7--phosphonoheptanoate (AP7; 10 ..mu..M-1 mM). These findings indicate that EAAS facilitate TCP binding, possibly through NMDA-type receptors. The observed interaction between the PCP receptor and EAARs may reflect the existence of a macromolecular receptor complex similar to that demonstrated for the benzodiazepines and GABA.« less

  18. 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.

  19. Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel

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

    Leeson, P.D.; Carling, R.W.; James, K.

    1990-05-01

    Displacement of (3H)MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of themore » nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo(x.y.z)alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.« less

  20. Post-weaning social isolation increases activity in a novel environment but decreases defensive burying and subchronic MK-801 enhances the activity but not the burying effect in rats.

    PubMed

    Simpson, Sarah M; Menard, Janet L; Reynolds, James N; Beninger, Richard J

    2010-03-01

    Subchronic treatment with a non-competitive glutamate NMDA-receptor antagonist [e.g., MK-801 or phencyclidine] or social isolation (SI) from weaning (age 21 days) to adulthood (age 56 days) produce deficits similar to some of the positive and negative symptoms of schizophrenia. Few studies have evaluated the effects of these treatments on emotional behavior. We hypothesized that subchronic MK-801, post-weaning SI or the two in combination would alter activity in a novel environment, anxiety-like behaviors in the elevated plus-maze, coping responses in the defensive burying paradigm and social behavior. In experiment 1, SI rats (n=17) showed increased locomotor activity when exposed to a novel environment, no change in plus-maze behavior and decreased defensive burying when compared to group housed rats (n=16). Subchronic MK-801 enhanced the increase in activity but not the decrease in burying in SI rats. Experiment 2 evaluated the effects on social behavior of post-weaning SI. The locomotor and burying results of experiment 1 were replicated and SI rats (n=9) were found to decrease orientation towards a novel conspecific social target when compared to group housed rats (n=8). The behavioral abnormalities of SI rats may be a manifestation of GABAergic dysfunction that has recently become evident in schizophrenia. (c) 2009 Elsevier Inc. All rights reserved.

  1. Olanzapine Prevents the PCP-induced Reduction in the Neurite Outgrowth of Prefrontal Cortical Neurons via NRG1

    PubMed Central

    Zhang, Qingsheng; Yu, Yinghua; Huang, Xu-Feng

    2016-01-01

    Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression; (2) if olanzapine affects the Akt-GSK3 signaling pathway; and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24 hours reduces both neurite length (28.5%) and the number of neurite branches (35.6%) in primary prefrontal cortical neuron cultures. PCP reduced protein and mRNA expressions of synaptophysin (24.9% and 23.2%, respectively) and PSD95 (31.5% and 21.4%, respectively), and the protein expression of p-Akt (26.7%) and p-GSK3β (35.2%). Olanzapine co-treatment prevented these PCP-induced effects in normal neurons but not in neurons from NRG1-knockout mice. These results indicate that NRG1 mediates the preventive effects of olanzapine on the PCP-induced impairment of neurite outgrowth and synaptic protein expression. This study provides potential targets for interventions on improving the efficacy of olanzapine on preventing cognitive deficits in schizophrenia. PMID:26781398

  2. 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

  3. Amphetamine-like effects of anorectics and related compounds in pigeons.

    PubMed

    Evans, S M; Johanson, C E

    1987-06-01

    Four pigeons were trained to discriminate injections of d-amphetamine (AMPH; 2.0 mg/kg i.m.) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. When drugs used therapeutically as anorectics were tested, they consistently produced greater than 80% of AMPH-appropriate responding. The order of potency for substituting for AMPH was: mazindol greater than AMPH = phenmetrazine = phentermine greater than chlorphentermine = phendimetrazine = diethylpropion greater than clortermine = mefenorex. Other anorectics such as phenylpropanolamine (0.3-30.0 mg/kg) and fenfluramine (1.0-17.0 mg/kg) only substituted partially for AMPH whereas benzphetamine (1.0-100.0 mg/kg) resulted primarily in saline-appropriate responding. Compounds related to AMPH in biochemical mechanism of action or psychomotor stimulant activity also were tested. Methylphenidate (0.1-3.0 mg/kg), piribedil (0.3-17.0 mg/kg) and nisoxetine (0.03-1.0 mg/kg) shared discriminative stimulus properties with AMPH whereas bupropion (1.0-30.0 mg/kg) and propylhexedrine (10.0-100.0 mg/kg) substituted for AMPH in two of three pigeons tested. In contrast, caffeine and fenetylline resulted principally in saline-appropriate responding. Compounds from pharmacological classes not related to AMPH, such as morphine, diazepam and phencyclidine, failed to substitute for AMPH. In general, compounds with anorectic and/or stimulant properties shared discriminative stimulus properties with AMPH.

  4. THE USE OF FRY (EMBALMING FLUID AND PCP-LACED CIGARETTES OR MARIJUANA STICKS) AMONG CRACK COCAINE SMOKERS

    PubMed Central

    PETERS, RONALD J.; WILLIAMS, MARK; ROSS, MICHAEL W.; ATKINSON, JOHN; McCURDY, SHERLY A.

    2010-01-01

    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 cross-sectional survey was conducted among 426 African-American crack users in Houston, Texas, to investigate the difference between those who concurrently reported lifetime (defined as at least one usage of fry in life) fry use and those who stated they never used fry. The data were analyzed using chi-square and logistic regression analyses. Fry users were significantly more likely than non-users to not have a casual sex partner (92% users vs. 84% non-users, p ≤ 0.05) and were more likely to have been diagnosed with gonorrhea in the past 12 months (9% users vs. 2% non-users, p ≤ 0.05). In addition fry users had significantly higher odds of currently trading sex for drugs (OR = 2.30, p ≤ 0.05), marijuana use (OR = 12.11, p ≤ 0.05), and codeine (syrup) use (OR = 8.10, p ≤ 0.05). These findings are important in determining the “cultural novelties” relative to crack and fry use among younger African Americans. PMID:19157045

  5. 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

  6. D-cycloserine adjuvant therapy to molindone in the treatment of schizophrenia.

    PubMed

    Rosse, R B; Fay-McCarthy, M; Kendrick, K; Davis, R E; Deutsch, S I

    1996-10-01

    This preliminary investigation examined the therapeutic efficacy of two doses of oral D-cycloserine (5 and 15 mg p.o. b.i.d.) administered as an adjuvant to molindone (150 mg p.o. q.d.) in the treatment of schizophrenia. D-Cycloserine is an agonist at the N-methyl-D-aspartate (NMDA) subclass of glutamate receptor complex. An NMDA agonist intervention was studied because of the schizophreniform psychosis precipitated by phencyclidine (PCP), which is a noncompetitive antagonist at the NMDA glutamate receptor. The PCP model of schizophrenia is regarded as the most comprehensive pharmacological model of this disorder. In this preliminary, placebo-controlled, double-blind, parallel-group study, the measures of treatment efficacy were the Brief Psychiatric Rating Scale, Schedule for the Assessment of Negative Symptoms, and Clinical Global Impression Scale. The final scores for each item of the outcome measures employed were based on the consensus of at least two trained raters who were present during each rating interview. In the 13 subjects evaluated, although the D-cycloserine was well tolerated, neither dose seemed to possess adjuvant therapeutic efficacy. However, since another recent report of nine patients with schizophrenia treated for 2 weeks with a slightly higher dose of D-cycloserine (50 mg/day) described significant clinical and neuropsychological improvement, further study of the adjuvant potential of slightly higher doses of D-cycloserine seems warranted. Additionally, there might be a therapeutic window for D-cycloserine dosing, as daily doses of 250 mg have been associated with symptom worsening.

  7. 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.

  8. 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

  9. Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states

    PubMed Central

    Arias, Hugo R.; Rosenberg, Avraham; Feuerbach, Dominik; Targowska-Duda, Katarzyna M.; Maciejewski, Ryszard; Jozwiak, Krzysztof; Moaddel, Ruin; Glick, Stanley D.; Wainer, Irving W.

    2013-01-01

    The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H] ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization. PMID:20303928

  10. An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function.

    PubMed

    Fone, Kevin C F

    2008-11-01

    As the 5-hydroxytryptamine(6) (5-HT(6)) receptor is almost exclusively expressed in the CNS, particularly in areas associated with learning and memory, many studies have examined its role in cognitive function in the rodent, as reviewed herein. Most studies, in healthy adult rats, report that 5-HT(6) receptor antagonists enhance retention of spatial learning in the Morris water maze, improve consolidation in autoshaping tasks and reverse natural forgetting in object recognition. Antagonists appear to facilitate both cholinergic and glutamatergic neurotransmission, reversing scopolamine- and NMDA receptor antagonist-induced memory impairments. Recent reports show that the 5-HT(6) receptor antagonist, PRX-07034, restores the impairment of novel object recognition produced in rats reared in social isolation, a neurodevelopmental model producing behavioural changes similar to several core symptoms seen in schizophrenia. The 5-HT(6) receptor antagonist, Ro 04-6790, modestly improved reversal learning in isolation reared but not group-housed controls in the water maze. Ro 04-6790 also improved novel object discrimination both in adult rats that received chronic intermittent phencyclidine and drug-naïve 18-month-old rats. However, more information on their effect in animal models of schizophrenia and Alzheimer's disease is required. Several selective high-affinity 5-HT(6) receptor agonists developed recently also improve object discrimination and extra-dimensional set-shifting behaviour. Thus both 5-HT(6) receptor agonist and antagonist compounds show promise as pro-cognitive agents in pre-clinical studies but the explanation for their paradoxical analogous effect is currently unclear, and is discussed in this article.

  11. 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.

  12. 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

  13. 'Legal highs'--novel and emerging psychoactive drugs: a chemical overview for the toxicologist.

    PubMed

    Gibbons, Simon

    2012-01-01

    'Legal highs' are psychoactive chemicals which are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. A survey of the internet was used to identify websites that are marketing 'legal highs' in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl-tryptamine. 'Legal highs' from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. 'Legal highs' are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with 'legal highs' is needed.

  14. Metabolism of designer drugs of abuse: an updated review.

    PubMed

    Meyer, Markus R; Maurer, Hans H

    2010-06-01

    This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years and is an update of a review published in 2005. The presented review contains data concerning the so-called 2C compounds (phenethylamine type) such as 4-bromo-2,5-dimethoxy-beta-phenethylamine (2C-B), 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I), 2,5-dimethoxy-4-methyl-beta-phenethylamine (2C-D), 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E), 4-ethylthio-2,5-dimethoxy-beta-phenethylamine (2C-T-2), and 2,5-dimethoxy-4-propylthio-beta-phenethylamine (2C-T-7), beta-keto designer drugs such as 2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (butylone, bk-MBDB), 2-ethylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (ethylone, bk-MDEA), 2-methylamino-1-(3,4-methylene notdioxy notphenyl)propan-1-one (methylone, bk-MDMA), and 2-methylamino-1-p-tolylpropane-1-one (mephedrone, 4-methyl-methcathinone), pyrrolidino notphenones such as 4-methyl-pyrrolidinobutyrophenone (MPBP) and alpha-pyrrolidinovalerophenone (PVP), phencyclidine-derived drugs such as N (1 phenylcyclohexyl) propanamine (PCPr), N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA), N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA), and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA), tryptamines such as 5-methoxy-N,N-diisopropyl nottryptamine (5-MeO-DIPT), and finally alpha-methylfentanyl (alpha-MF) and 3-methylfentanyl (3-MF). Papers have been considered and reviewed on the identification of in vivo or in vitro human or animal metabolites and the cytochrome P450 or monoamineoxidase isoenzyme-dependent metabolism.

  15. 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.

  16. In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

    PubMed

    Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping; Urban, Daniel J; White, Kate L; Giguere, Patrick M; Doak, Allison K; Bernstein, Alison I; Stout, Kristen A; Park, Su Mi; Rodriguiz, Ramona M; Gray, Bradley W; Hyatt, William S; Norwood, Andrew P; Webster, Kevin A; Gannon, Brenda M; Miller, Gary W; Porter, Joseph H; Shoichet, Brian K; Fantegrossi, William E; Wetsel, William C; Roth, Bryan L

    2016-01-01

    The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

  17. Neonatal NMDA receptor blockade alters anxiety- and depression-related behaviors in a sex-dependent manner in mice.

    PubMed

    Amani, Mohammad; Samadi, Hanieh; Doosti, Mohammad-Hossein; Azarfarin, Maryam; Bakhtiari, Amir; Majidi-Zolbanin, Naime; Mirza-Rahimi, Mehrdad; Salari, Ali-Akbar

    2013-10-01

    There is increasing evidence that N-methyl-D-aspartate (NMDA) receptor blockade in the neonatal period has a long-lasting influence on brain and behavior development and has been linked to an increased risk for neuropsychiatric disorders in later life. We sought to determine whether postnatal NMDA receptor blockade can affect normal development of body weight, corticosterone levels, anxiety- and depression-related behaviors in male and female mice in adulthood. For this purpose, male and female NMRI mice were treated with either saline or phencyclidine (PCP; 5 and 10 mg/kg, s.c.) on postnatal days (PND) 7, 9, and 11, and then subjected to different behavioral tests, including open field, elevated plus-maze, elevated zero-maze, light-dark box, tail suspension test and forced swimming test in adulthood. The results indicated that neonatal PCP treatment reduced body weight during neonatal and adulthood periods, and did not alter baseline corticosterone levels in both male and female mice. Moreover, this study obtained some experimental evidence showing the PCP at dose of 10 mg/kg increases stress-induced corticosterone levels, anxiety- and depression-related behaviors in males, while decreasing levels of anxiety without any significant effect on depression in female mice in adulthood. These data support the argument that neonatal NMDA receptor blockade can lead to behavioral abnormalities and psychiatric diseases in adulthood. Collectively, our findings suggest that neonatal exposure to PCP may have profound effects on the development of anxiety- and depression-related behaviors in a sex- and dose-dependent manner in mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. A Retrospective Analysis of Urine Drugs of Abuse Immunoassay True Positive Rates at a National Reference Laboratory.

    PubMed

    Johnson-Davis, Kamisha L; Sadler, Aaron J; Genzen, Jonathan R

    2016-03-01

    Urine drug screens are commonly performed to identify drug use or monitor adherence to drug therapy. The purpose of this retrospective study was to evaluate the true positive and false positive rates of one of our in-house urine drug screen panels. The urine drugs of abuse panel studied consists of screening by immunoassay then positive immunoassay results were confirmed by mass spectrometry. Reagents from Syva and Microgenics were used for the immunoassay screen. The screen was performed on a Beckman AU5810 random access automated clinical analyzer. The percent of true positives for each immunoassay was determined. Agreement with previously validated GC-MS or LC-MS-MS confirmatory methods was also evaluated. There were 8,825 de-identified screening results for each of the drugs in the panel, except for alcohol (N = 2,296). The percent of samples that screened positive were: 10.0% for amphetamine/methamphetamine/3,4-methylenedioxy-methamphetamine (MDMA), 12.8% for benzodiazepines, 43.7% for opiates (including oxycodone) and 20.3% for tetrahydrocannabinol (THC). The false positive rate for amphetamine/methamphetamine was ∼14%, ∼34% for opiates (excluding oxycodone), 25% for propoxyphene and 100% for phencyclidine and MDMA immunoassays. Based on the results from this retrospective study, the true positive rate for THC drug use among adults were similar to the rate of illicit drug use in young adults from the 2013 National Survey; however, our positivity rate for cocaine was higher than the National Survey. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use?

    PubMed

    McGregor, I S; Callaghan, P D; Hunt, G E

    2008-05-01

    Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the 'social neuropeptide' oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders.

  20. Cross-site strain comparison of pharmacological deficits in the touchscreen visual discrimination test.

    PubMed

    Mohler, Eric G; Ding, Zhiyong; Rueter, Lynne E; Chapin, Douglas; Young, Damon; Kozak, Rouba

    2015-11-01

    The low rate of success for identifying effective treatments for cognitive dysfunction has prompted recent efforts to improve pharmaceutical discovery and development. In particular, investigators have emphasized improving translation from pre-clinical to clinical research. A specific area of focus has been touchscreen technology; this computer-automated behavioral testing method provides an objective assessment of performance that can be used across species. As part of a larger multi-site study with partners from the Innovative Medicines Initiative (IMI), two US sites, AbbVie and Pfizer, conducted a cross-site experiment with a common protocol for the visual discrimination (VD) task using identical testing equipment, stimuli, and rats of the same strains, sex, and age from the same supplier. As most touchscreen-based rodent experiments have used Lister-Hooded rats that are not readily available outside of Europe, a strain comparison with male Long-Evans rats was conducted as part of the study. Rats were trained for asymptotic performance, and test sessions were performed once per week in a full crossover design with cognition-impairing drugs. Drugs tested were phencyclidine and S-ketamine (N-methyl-D-aspartate (NMDA) antagonists), D-amphetamine (indirect dopamine agonist), and scopolamine (muscarinic antagonist). Satellite brain and plasma samples were taken to confirm appropriate exposures. Results indicate that both rat strains show similar patterns of impairment, although Lister-Hooded rats were more sensitive than Long-Evans rats to three out of four drugs tested. This suggests that researchers should fully explore dose-response relationships in their strain of choice and use care in the interpretation of reversal of cognitive impairment.

  1. Male rats treated with subchronic PCP show intact olfaction and enhanced interest for a social odour in the olfactory habituation/dishabituation test.

    PubMed

    Tarland, Emilia; Brosda, Jan

    2018-06-01

    The olfactory system participates in many sensory processes, and olfactory endophenotypes appear in a variety of neurological disorders such as Alzheimer's and Parkinson's disease, depression and schizophrenia. Social withdrawal is a core negative symptom of schizophrenia and animal models have proven to be invaluable for studying the neurobiological mechanisms and cognitive processes behind the formation of social relationships. The subchronic phencyclidine (PCP) rat model is a validated model for negative symptoms of schizophrenia, such as impaired sociability. However, the complete range of social behaviour and deficits in the model are still not fully understood. Intact rodent olfaction is essential for a wide range of social behaviour and disrupted olfactory function could have severe effects on social communication and recognition. In order to examine the olfactory ability of male rats treated with subchronic PCP, we conducted an olfactory habituation/dishabituation test including both non-social and social odours. The subchronic PCP-treated rats successfully recognized and discriminated among the odours, indicative of intact olfaction. Interestingly, the subchronic PCP-treated rats showed greater interest for a novel social odour compared to the saline-treated rats and the rationale remains to be elucidated. Our data indicate that subchronic PCP treatment does not disrupt olfactory function in male rats. By ruling out impaired olfaction as cause for the poor social interaction performance in subchronic PCP-treated rats, our data supports the use of NMDA receptor antagonists to model the negative symptoms of schizophrenia. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity, acetylcholine release and dopamine metabolism in the nucleus accumbens.

    PubMed

    Del Arco, A; Mora, F; Mohammed, A H; Fuxe, K

    2007-02-01

    The aim of the present study was to investigate the effects of stimulation of D2 receptors in the prefrontal cortex (PFC) on spontaneous motor activity and the hyperactivity induced by the psychomimetic phencyclidine (PCP). In addition, the effects of prefrontal D2 stimulation under PCP treatment on dialysate concentrations of acetylcholine, choline, dopamine, DOPAC and HVA in the nucleus accumbens were also investigated. Sprague-Dawley male rats were implanted with guide cannulae to perform bilateral injections into the medial PFC of the D2 agonist quinpirole (1.5 and 5 microg/side). Horizontal and vertical spontaneous motor activity and the motor activity induced by systemic injections of the PCP (5 mg/kg i.p.) were monitored in the open field. PFC injections of quinpirole (1.5 and 5 microg/side) significantly decreased horizontal and vertical spontaneous motor activity in a dose-related manner. These effects were blocked by the D2 antagonist raclopride (5 microg/side). Microinjections of quinpirole (1.5 and 5 microg/side) into the PFC also significantly attenuated the hyperactivity produced by PCP (5 mg/kg i.p.). PCP also increased dialysate concentrations of acetylcholine, and dopamine metabolites in the nucleus accumbens. These increases were also reduced by injections of quinpirole (5 microg/side) into the PFC. These results suggest that the stimulation of prefrontal D2 receptors plays an inhibitory role in regulating spontaneous and PCP-induced motor activity and also in the neurochemical changes produced by PCP in the nucleus accumbens.

  3. Central N-acetyl aspartylglutamate deficit: a possible pathogenesis of schizophrenia.

    PubMed

    Tsai, Shih-Jen

    2005-09-01

    The "glutamate hypothesis" of schizophrenia has emerged from the finding that phencyclidine (PCP) induces psychotic-like behaviors in rodents, possibly by blocking the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, thereby causing increased glutamate release. N-acetyl aspartylglutamate (NAAG), an endogenous peptide abundant in mammalian nervous systems, is localized in certain brain cells, including cortical and hippocampal pyramidal neurons. NAAG is synthesized from N-acetylaspartate (NAA) and glutamate, and NAA availability may limit the rate of NAAG synthesis. Although NAAG is known to have some neurotransmitter-like functions, NAA does not. NAAG is a highly selective agonist of the type 3 metabotropic glutamate receptor (mGluR3, a presynaptic autoreceptor) and can inhibit glutamate release. In addition, at low levels, NAAG is an NMDA receptor antagonist, and blocking of NMDA receptors may increase glutamate release. Taken together, low central NAAG levels may antagonize the effect of glutamate at NMDA receptors and decrease its agonistic effect on presynaptic mGluR3; both activities could increase glutamate release, similar to the increase demonstrated in the PCP model of schizophrenia. In this report, it is suggested that the central NAAG deficit, possibly through decreased synthesis or increased degradation of NAAG, may play a role in the pathogenesis of schizophrenia. Evidence is presented and discussed from magnetic resonance, postmortem, animal model, schizophrenia treatment, and genetic studies. The central NAAG deficit model of schizophrenia could explain the disease process, from the perspectives of both neurodevelopment and neurodegeneration, and may point to potential treatments for schizophrenia.

  4. Neurodevelopmental Expression Profile of Dimeric and Monomeric Group 1 mGluRs: Relevance to Schizophrenia Pathogenesis and Treatment.

    PubMed

    Lum, Jeremy S; Fernandez, Francesca; Matosin, Natalie; Andrews, Jessica L; Huang, Xu-Feng; Ooi, Lezanne; Newell, Kelly A

    2016-10-10

    Group 1 metabotropic glutamate receptors (mGluR1/mGluR5) play an integral role in neurodevelopment and are implicated in psychiatric disorders, such as schizophrenia. mGluR1 and mGluR5 are expressed as homodimers, which is important for their functionality and pharmacology. We examined the protein expression of dimeric and monomeric mGluR1α and mGluR5 in the prefrontal cortex (PFC) and hippocampus throughout development (juvenile/adolescence/adulthood) and in the perinatal phencyclidine (PCP) model of schizophrenia. Under control conditions, mGluR1α dimer expression increased between juvenile and adolescence (209-328%), while monomeric levels remained consistent. Dimeric mGluR5 was steadily expressed across all time points; monomeric mGluR5 was present in juveniles, dramatically declining at adolescence and adulthood (-97-99%). The mGluR regulators, Homer 1b/c and Norbin, significantly increased with age in the PFC and hippocampus. Perinatal PCP treatment significantly increased juvenile dimeric mGluR5 levels in the PFC and hippocampus (37-50%) but decreased hippocampal mGluR1α (-50-56%). Perinatal PCP treatment also reduced mGluR1α dimer levels in the PFC at adulthood (-31%). These results suggest that Group 1 mGluRs have distinct dimeric and monomeric neurodevelopmental patterns, which may impact their pharmacological profiles at specific ages. Perinatal PCP treatment disrupted the early expression of Group 1 mGluRs which may underlie neurodevelopmental alterations observed in this model.

  5. 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

  6. Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers.

    PubMed

    Gouzoulis-Mayfrank, E; Heekeren, K; Neukirch, A; Stoll, M; Stock, C; Obradovic, M; Kovar, K-A

    2005-11-01

    Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT2A agonist DMT and the glutamate N-methyl-D-aspartate (NMDA) antagonist (S)-ketamine. Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine. The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.

  7. Drug Violations and Aviation Accidents: Findings from the U.S. Mandatory Drug Testing Programs

    PubMed Central

    Li, Guohua; Baker, Susan P.; Zhao, Qi; Brady, Joanne E.; Lang, Barbara H.; Rebok, George W.; DiMaggio, Charles

    2012-01-01

    Aims To assess the role of drug violations in aviation accidents. Design Case-control analysis. Setting Commercial aviation in the United States. Participants Aviation employees who were tested for drugs during 1995 through 2005 under the post-accident testing program (cases, n=4,977) or under the random testing program (controls, n=1,129,922). Measurements Point prevalence of drug violations, odds ratio of accident involvement, and attributable risk in the population. A drug violation was defined as a confirmed positive test for marijuana (≥ 50 ng/ml), cocaine (≥ 300 ng/ml), amphetamines (≥1000 ng/ml), opiates (≥ 2000 ng/ml), or phencyclidine (≥ 25 ng/ml). Findings The prevalence of drug violations was 0.64% [95% confidence interval (CI), 0.62–0.65%] in random drug tests and 1.82% (95% CI, 1.47–2.24%) in post-accident tests. The odds of accident involvement for employees who tested positive for drugs was almost three times the odds for those who tested negative (odds ratio 2.90, 95% CI, 2.35–3.57), with an estimated attributable risk of 1.2%. Marijuana accounted for 67.3% of the illicit drugs detected. The proportion of illicit drugs represented by amphetamines increased progressively during the study period, from 3.4% in 1995 to 10.3% in 2005 (p<0.0001). Conclusions Use of illicit drugs by aviation employees is associated with a significantly increased risk of accident involvement. Due to the very low prevalence, drug violations contribute to only a small fraction of aviation accidents. PMID:21306594

  8. Combined NMDA Inhibitor Use in a Patient With Multisubstance-induced Psychotic Disorder.

    PubMed

    Caloro, Matteo; Calabrò, Giuseppa; de Pisa, Eleonora; Rosini, Enrico; Kotzalidis, Georgios D; Lonati, Davide; Locatelli, Carlo Alessandro; Papa, Pietro; Schifano, Fabrizio; Girardi, Paolo

    : Novel psychoactive substance use is a major social concern. Their use may elicit or uncover unpredictably as yet undescribed clinical pictures. We aimed to illustrate a multisubstance use case indistinguishable from paranoid schizophrenia, so to alert clinicians on possibly misdiagnosing substance-induced psychotic disorders. We describe a case of a 32-year-old man who started at 18 years with cannabinoids and ketamine, and is currently using N-methyl-D-aspartate (NMDA) antagonists. At age 23, he developed social withdrawal after being assaulted by a stranger, but did not consult psychiatrists until age 26; during this period, he was using internet-purchased methoxetamine and ketamine, and was persecutory, irritable, suspicious, and insomniac and discontinued all received medical prescriptions. He added dextromethorphan to his list of used substances. At age 31, while using phencyclidine, and, for the first time, methoxphenidine, he developed a religious delusion, involving God calling him to reach Him, and the near-death experiences ensured by NMDA antagonists backed his purpose. He received Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnosis of multisubstance-induced psychotic disorder and was hospitalized 8 times, 6 of which after visiting the emergency room due to the development of extreme anguish, verbal and physical aggression, and paranoia. He reportedly used methoxphenidine, methoxyphencyclidine, ethylnorketamine, norketamine, and deschlorketamine, to achieve near-death experiences, and eventually to reach God in heavens. This case points to the need for better control of drugs sold on the internet. It also illustrates that people using NMDA antagonists may present clinical pictures indistinguishable from those of major psychoses and are likely to be misdiagnosed.

  9. Towards the development of improved tests for negative symptoms of schizophrenia in a validated animal model.

    PubMed

    Sahin, Ceren; Doostdar, Nazanin; Neill, Joanna C

    2016-10-01

    Negative symptoms in schizophrenia remain an unmet clinical need. There is no licensed treatment specifically for this debilitating aspect of the disorder and effect sizes of new therapies are too small to make an impact on quality of life and function. Negative symptoms are multifactorial but often considered in terms of two domains, expressive deficit incorporating blunted affect and poverty of speech and avolition incorporating asociality and lack of drive. There is a clear need for improved understanding of the neurobiology of negative symptoms which can be enabled through the use of carefully validated animal models. While there are several tests for assessing sociability in animals, tests for blunted affect in schizophrenia are currently lacking. Two paradigms have recently been developed for assessing negative affect of relevance to depression in rats. Here we assess their utility for studying negative symptoms in schizophrenia using our well validated model for schizophrenia of sub-chronic (sc) treatment with Phencyclidine (PCP) in adult female rats. Results demonstrate that sc PCP treatment produces a significant negative affect bias in response to a high value reward in the optimistic and affective bias tests. Our results are not easily explained by the known cognitive deficits induced by sc PCP and support the hypothesis of a negative affective bias in this model. We suggest that further refinement of these two tests will provide a means to investigate the neurobiological basis of negative affect in schizophrenia, thus supporting the assessment of efficacy of new targets for this currently untreated symptom domain. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. [Acting out and psychoactive substances: alcohol, drugs, illicit substances].

    PubMed

    Gillet, C; Polard, E; Mauduit, N; Allain, H

    2001-01-01

    In humans, some psychotropic agents (alcohol, drugs, illicit substances) have been suggested to play a role in the occurrence of major behavioural disorders, mainly due to the suppression of psychomotor inhibition. Behavioural disinhibition is a physiological mechanism which allows humans to behave appropriately according to a given environmental situation. The behavioural disinhibition induced by either therapeutic dosage or misuse involves the loss of restraint over certain types of social behaviour and may increase the risk of auto or hetero-aggression and acting out. The increased use of psychotropic agents in recent years and the occurrence of unwanted effects are worrying and must be detected and evaluated. The objective of the present study was to establish a causal relationship between psychoactive substance use and occurrence of major behavioural disorders, such as paradoxical rage reactions and suicidal behaviour, based on a literature analysis. It consisted of reviewing reports of drug-induced violent reactions in healthy volunteers and demonstrating, where possible, a cause-effect relationship. Patients with schizophrenia and psychopathic personalities were not included in our study since psychiatric comorbidity could influence behavioural responses. Psychotropic agents included drugs, licit and illicit substances already associated with violence in the past. Many reports used the "Go/No Go test" to evaluate the disinhibiting effect of psychotropic substances; this allows the "cognitive mapping" of drugs. The results suggest that only alcohol, antidepressants, benzodiazepines and cocaïne are related to aggressive behaviour. The best known precipitant of behavioural disinhibition is alcohol, which induces aggressive behaviour. However, there are large differences between individuals, and attentional mechanisms are now recognised as being important in mediating the effects of alcohol. Suicidal tendency as an adverse antidepressant reaction is rare, especially with atypical antidepressants. However, the risk of acting out exists and the responsibility of antidepressant agents in the genesis of suicidal tendencies is now established. The disinhibiting effects of benzodiazepines are well-known and proven by clinical trials. It's a "model" of acting out, and the causal relationship is undeniable. That cocaïne is related to violent behaviour is demonstrated by its pharmacological actions on CNS. The chronic use of cocaïne induces "a limbic dyscontrol syndrome" based on the altered activity of limbic structures. On the contrary, we could not demonstrate a causal relationship between aggression and either cannabis, ecstasy or phencyclidine. Cannabis abusers look particularly for euphoria and relaxing effects. Aggression as an adverse cannabis reaction is very rare and occurs in most cases in association with other drugs and in predisposed individuals. Ecstasy use may lead to long-term alterations of neuronal function in the human CNS and cause psychiatric disorders. However, there is insufficient information about long-term use of ecstasy to estimate its role in the occurrence of behavioural disorders. Clinical and forensic assumptions about phencyclidine and violence were not warranted. However, the substance-effect relationships can be criticized in the case of alcohol, antidepressants, benzodiazepines and cocaïne. In fact, individual, social and psychiatric factors exert an influence on behaviour that is superior to the pharmacological effect of psychotropic agents. The most important parameter in drug-induced behavioural disinhibition is dosage, but mode of administration is also important. In addition, polysubstance abuse is very common. Substances may be taken simultaneously and alcohol is frequently combined with drugs. The combinations of substances result in multiple interactions, and very little is known about the effects of these interactions on violence in humans. Co-occurrence of substance abuse and other mental disorders is also very frequent. Multiple substance abuse should be avoided, because potential interactions between two or more drugs are more likely to cause violent behaviour. In the future, a specific treatment of these deleterious phenomena will have to be considered in order to reduce drug-induced iatrogenic behavioural disorders.

  11. Functional recovery of supersensitive dopamine receptors after intrastriatal grafts of fetal substantia nigra

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

    Dawson, T.M.; Dawson, V.L.; Gage, F.H.

    1991-03-01

    Interruption of the ascending dopamine neurons of the nigrostriatal pathway, by 6-hydroxydopamine (6-OHDA) lesion in rats, produced a significant loss of the dopamine transport complexes labeled with the phencyclidine derivative (3H)BTCP. This loss of dopamine innervation in the striatum was present at least 12 to 14 months after lesioning and was functionally manifested by ipsilateral rotation of the animals in response to amphetamine. In these same animals, in comparison to controls, there was a significant increase in the number (Bmax) of (3H)SCH 23390-labeled D-1 receptors in the striatum (36.7%) and the substantia nigra (35.1%) and a 54.4% increase in themore » number (Bmax) of (3H)sulpiride-labeled striatal D-2 receptors without an apparent change in affinity (Kd). Ten to twelve months after the transplantation of homologous fetal substantia nigra into the denervated striatum, there was a significant decrease in amphetamine-induced turning behavior. In these animals, there was an ingrowth of dopamine nerve terminals in the striatum as demonstrated by a return of (3H)BTCP binding. Accompanying this reinnervation was the normalization of D-1 and D-2 receptors to control values in the striatum as well as the return of D-1 receptors to prelesion densities in the substantia nigra. In a subgroup of transplanted rats, amphetamine continued to induce ipsilateral turning. In these animals both D-1 and D-2 receptors remained supersensitive. These results support the hypothesis that the functional recovery of transplanted animals is due, in part, to reinnervation of the striatum. In addition, long-term alterations in receptor density may be related to the behavioral deficits that are associated with the 6-OHDA-lesioned rat.« less

  12. Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.

    PubMed

    Huang, Mei; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-11-01

    Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Adulteration of urine by "Urine Luck".

    PubMed

    Wu, A H; Bristol, B; Sexton, K; Cassella-McLane, G; Holtman, V; Hill, D W

    1999-07-01

    In vitro adulterants are used to invalidate assays for urine drugs of abuse. The present study examined the effect of pyridinium chlorochromate (PCC) found in the product "Urine Luck". PCC was prepared and added to positive urine controls at concentrations of 0, 10, 50, and 100 g/L. The controls were assayed for methamphetamine, benzoylecgonine (BE), codeine and morphine, tetrahydrocannabinol (THC), and phencyclidine (PCP) with the Emit II (Syva) and Abuscreen Online (Roche) immunoassays, and by gas chromatography/mass spectrometry (GC/MS). Two tests were also developed to detect PCC in urine: a spot test to detect chromate ions using 10 g/L 1,5-diphenylcarbazide as the indicator, and a GC/MS assay for pyridine. We tested 150 samples submitted for routine urinalysis, compliance, and workplace drug testing for PCC, using these assays. Response rates decreased at 100 g/L PCC for all Emit II drug assays and for the Abuscreen morphine and THC assays. In contrast, the Abuscreen amphetamine assay produced apparently higher results, and no effect was seen on the results for BE or PCP. The PCC did not affect the GC/MS recovery of methamphetamine, BE, PCP, or their deuterated internal standards, but decreased GC/MS recovery of the opiates at both intermediate (50 g/L) and high (100 g/L) PCC concentrations and apparent concentrations of THC and THC-d3 at all PCC concentrations. Two of 50 samples submitted for workplace drug testing under chain-of-custody conditions were positive for PCC, whereas none of the remaining 100 specimens submitted for routine urinalysis or compliance drug testing were positive. PCC is an effective adulterant for urine drug testing of THC and opiates. Identification of PCC use can be accomplished with use of a spot test for the oxidant.

  14. Prenatal Methamphetamine Exposure and Neonatal and Infant Neurobehavioral Outcome: Results from the IDEAL Study

    PubMed Central

    Kiblawi, Zeina N.; Smith, Lynne M.; Diaz, Sabrina D.; LaGasse, Linda L.; Derauf, Chris; Newman, Elana; Shah, Rizwan; Arria, Amelia; Huestis, Marilyn; Haning, William; Strauss, Arthur; DellaGrotta, Sheri; Dansereau, Lynne M.; Neal, Charles; Lester, Barry

    2013-01-01

    Background Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How MA use during pregnancy affects neonatal and infant neurobehavior is unknown. Methods The Infant Development, Environment, and Lifestyle (IDEAL) study screened 34,833 subjects at 4 clinical centers. 17,961 were eligible and 3,705 were consented, among which 412 were enrolled for longitudinal follow-up. Exposed subjects were identified by self-report and/or GC/MS confirmation of amphetamine and metabolites in meconium. Comparison subjects were matched (race, birth weight, maternal education, insurance), denied amphetamine use and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, or phencyclidine. The NICU Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life and again at one month to 380 enrollees (185 exposed, 195 comparison). ANOVA tested exposure effects on NNNS summary scores at birth and one month. GLM repeated measures analysis assessed the effect of MA exposure over time on the NNNS scores with and without covariates. Results By one month of age, both groups demonstrated higher quality of movement (P=.029), less lethargy (P=.001), and fewer asymmetric reflexes (P=.012), with no significant differences in NNNS scores between the exposed and comparison groups. Over the first month of life, arousal increased in exposed infants but decreased in comparison infants (p=.031) and total stress was decreased in exposed infants with no change in comparison infants (p=.026). Conclusions Improvement in total stress and arousal were observed in MA-exposed newborns by one month of age relative to the newborn period. PMID:24588296

  15. 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.

  16. Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors' in Mice

    PubMed Central

    Vitucci, Daniela; Di Giorgio, Annabella; Napolitano, Francesco; Pelosi, Barbara; Blasi, Giuseppe; Errico, Francesco; Attrotto, Maria Teresa; Gelao, Barbara; Fazio, Leonardo; Taurisano, Paolo; Di Maio, Anna; Marsili, Valentina; Pasqualetti, Massimo; Bertolino, Alessandro; Usiello, Alessandro

    2016-01-01

    Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia. PMID:26228524

  17. Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.

    PubMed

    Vitucci, Daniela; Di Giorgio, Annabella; Napolitano, Francesco; Pelosi, Barbara; Blasi, Giuseppe; Errico, Francesco; Attrotto, Maria Teresa; Gelao, Barbara; Fazio, Leonardo; Taurisano, Paolo; Di Maio, Anna; Marsili, Valentina; Pasqualetti, Massimo; Bertolino, Alessandro; Usiello, Alessandro

    2016-02-01

    Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.

  18. 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.

  19. 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.

  20. A practical approach to determination of laboratory GC-MS limits of detection.

    PubMed

    Underwood, P J; Kananen, G E; Armitage, E K

    1997-01-01

    Determination of limit of detection (LOD) values in a forensic laboratory serves a fundamental forensic requirement for assay performance. In addition to demonstrating assay capability, LOD values can also be used to fulfill certification requirements of a high-volume forensic drug laboratory. The LOD was defined as the lowest concentration of drug that the laboratory can detect in a specimen with forensic certainty at a minimum of 85% of the time. Overall batch acceptance criteria included acceptable quantitation of control materials (within 20% of target), acceptable chromatography (symmetry, peak integration, peak shape, peak, and baseline resolution), retention time within +/-1% of the extracted standard, and mass ion ratios within +/-20% of the extracted standard mass ion ratios. Individual specimen acceptance criteria were the same as the batch acceptance criteria excluding the quantitation requirement. Data were collected from all instruments on different runs. A minimum of ten data points was required for each certified instrument, and a minimum of 85% of data points was acceptable. Quantitation within +/-20% of the LOD concentration was not required, but acceptable mass ratios were required. Data points with poor chromatography (internal standard failed mass ratios; interference of the baseline, for example, shoulders; asymmetry; and baseline resolution) was omitted from the acceptable rate calculation. Data points with good chromatography with failed mass ion ratios were included in the acceptable rate calculation. With these criteria, we established the following LODs: 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid, 2 ng/mL; benzoylecgonine, 5 ng/mL; phencyclidine, 2.5 ng/mL; amphetamine, 150 ng/mL; methamphetamine, 100 ng/mL; codeine, 500 ng/mL; and morphine, 1000 ng/mL.

  1. 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.

  2. Neuropharmacology of light-induced locomotor activation.

    PubMed

    Amato, Davide; Pum, Martin E; Groos, Dominik; Lauber, Andrea C; Huston, Joseph P; Carey, Robert J; de Souza Silva, Maria A; Müller, Christian P

    2015-08-01

    Presentation of non-aversive light stimuli for several seconds was found to reliably induce locomotor activation and exploratory-like activity. Light-induced locomotor activity (LIA) can be considered a convenient simple model to study sensory-motor activation. LIA was previously shown to coincide with serotonergic and dopaminergic activation in specific cortical areas in freely moving and anesthetized animals. In the present study we explore the neuropharmacology of LIA using a receptor antagonist/agonist approach in rats. The non-selective 5-HT2-receptor antagonist ritanserin (1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. Selective antagonism of either the 5-HT2A-receptor by MDL 11,939 (0.1-0.4 mg/kg, i.p.), or the 5-HT2C-receptor by SDZ SER 082 (0.125-0.5 mg/kg, i.p.), alone or in combination, had no significant influence on LIA. Also the selective 5-HT1A-receptor antagonist, WAY 100635 (0.4 mg/kg, i.p.) did not affect LIA. Neither did the preferential dopamine D2-receptor antagonist, haloperidol (0.025-0.1 mg/kg, i.p.) nor the D2/D3-receptor agonist, quinpirole (0.025-0.5 mg/kg, i.p.) affect the expression of LIA. However, blocking the glutamatergic NMDA-receptor with phencyclidine (PCP, 1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. This effect was also observed with ketamine (10 mg/kg, i.p.). These findings suggest that serotonin and dopamine receptors abundantly expressed in the cortex do not mediate light-stimulus triggered locomotor activity. PCP and ketamine effects, however, suggest an important role of NMDA receptors in LIA. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. How does active substance use at psychiatric admission impact suicide risk and hospital length-of-stay?

    PubMed

    Miller, Keith A; Hitschfeld, Mario J; Lineberry, Timothy W; Palmer, Brian A

    2016-01-01

    Despite their high prevalence, little is known about the effects of substance use disorders and active substance use on the suicide risk or length-of-stay of psychiatric inpatients. This study examines the relationship between active substance use at the time of psychiatric hospitalization and changes in suicide risk measures and length-of-stay. Admission and discharge ratings on the Suicide Status Form-II-R, diagnoses, and toxicology data from 2,333 unique psychiatric inpatients were examined. Data for patients using alcohol, tetrahydrocannabinol, methamphetamines, cocaine, benzodiazepines, opiates, barbiturates, phencyclidine, and multiple substances on admission were compared with data from 1,426 admissions without substance use. Patients with substance use by toxicology on admission had a 0.9 day shorter length-of-stay compared to toxicology-negative patients. During initial nurse evaluation on the inpatient unit, these patients reported lower suicide measures (i.e., suicidal ideation frequency, overall suicide risk, and wish-to-die). No significant between-group differences were seen at discharge. Patients admitted with a substance use disorder diagnosis had a 1.0 day shorter length-of-stay than those without, while those with a substance use disorder diagnosis and positive toxicology reported the lowest measures of suicidality on admission. These results remained independent of psychiatric diagnosis. For acute psychiatric inpatients, suicide risk is higher and length-of-stay is longer in patients with substance use disorders who are NOT acutely intoxicated compared with patients without a substance use disorder. Toxicology-positive patients are less suicidal on admission and improve faster than their toxicology-negative counterparts. This study gives support to the clinical observation that acutely intoxicated patients may stabilize quickly with regard to suicidal urges and need for inpatient care.

  4. 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

  5. A novel screening method for 64 new psychoactive substances and 5 amphetamines in blood by LC-MS/MS and application to real cases.

    PubMed

    Vaiano, Fabio; Busardò, Francesco P; Palumbo, Diego; Kyriakou, Chrystalla; Fioravanti, Alessia; Catalani, Valeria; Mari, Francesco; Bertol, Elisabetta

    2016-09-10

    Identification and quantification of new psychoactive substances (NPS), both in biological and non-biological samples, represent a hard challenge for forensic toxicologists. NPS are increasingly emerging on illegal drug market. Many cases of co-consumption of NPS and other substances have also been reported. Hence, the development of analytical methods aiming at the detection of a broad-spectrum of compounds (NPS and "traditional" drugs) could be helpful. In this paper, a fully validated screening method in blood for the simultaneous detection of 69 substances, including 64 NPS (28 synthetic cannabinoids, 19 synthetic cathinones, 5 phenethylamines, 3 indanes, 2 piperazines, 2 tryptamines, 2 phencyclidine, methoxetamine, ketamine and its metabolite) and 5 amphetamines (amphetamine, methamphetamine, MDMA, MDA, 3,4-methylenedioxy-N-ethylamphetamine - MDEA-) by a dynamic multiple reaction monitoring analysis through liquid chromatography - tandem mass spectrometry (LC-MS/MS) is described. This method is very fast, easy to perform and cheap as it only requires the deproteinization of 200μL of blood sample with acetonitrile. The chromatographic separation is achieved with a C18 column. The analysis is very sensitive, with limits of quantification ranging from 0.1 to 0.5ng/mL. The method is linear from 1 to 100ng/mL and the coefficient of determination (R(2)) was always above 0.9900. Precision and accuracy were acceptable at any quality control level and recovery efficiency range was 72-110%. Matrix effects did not negatively affect the analytical sensitivity. This method was successfully applied to three real cases, allowing identification and quantification of: mephedrone and methamphetamine (post-mortem); ketamine, MDMA and MDA (post-mortem); AB-FUBINACA (ante-mortem). Copyright © 2016 Elsevier B.V. All rights reserved.

  6. [3H]MK-801 binding sites in post-mortem human frontal cortex.

    PubMed

    Kornhuber, J; Mack-Burkhardt, F; Kornhuber, M E; Riederer, P

    1989-03-29

    The binding of [3H]MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) was investigated in extensively washed homogenates of post-mortem human frontal cortex. The association of [3H]MK-801 proceeded slowly (t1/2 = 553 min) and reached equilibrium only after a prolonged incubation (greater than 24 h). The dissociation of [3H]MK-801 from the binding site was also slow (t1/2 = 244 min). Glutamate, glycine and magnesium markedly increased the rate of association (t1/2 = 14.8 min) and dissociation (t1/2 = 36.5 min). At equilibrium, the binding was not altered by these substances. Specific binding was linear with protein concentration, was saturable, reversible, stereoselective, heat-labile and was nearly absent in the white matter. Scatchard analysis of the saturation curves obtained at equilibrium indicated that there was a high-affinity (Kd1 1.39 +/- 0.21 nM, Bmax1 0.483 +/- 0.084 pmol/mg protein) and a low-affinity (Kd2 116.25 +/- 50.79 nM, Bmax2 3.251 +/- 0.991 pmol/mg protein) binding site. All competition curves obtained with (+)-MK-801, (-)-MK-801, phencyclidine and ketamine had Hill coefficients of less than unity and were best explained by a two-site model. Thus, our results demonstrate the presence of binding sites for MK-801 in post-mortem human brains and provide evidence for binding site heterogeneity. Furthermore, glutamate, glycine and magnesium accelerate the association and dissociation of [3H]MK-801 to and from its binding sites. The results add support to the hypothesis that MK-801, glutamate, glycine and magnesium all bind to different sites on the NMDA receptor-ion channel complex.

  7. A Comparative Study between the Effect of Combined Local Anesthetic and Low-dose Ketamine with Local Anesthetic on Postoperative Complications after Impacted Third Molar Surgery.

    PubMed

    Kumar, Anuj; Kale, Tejraj Pundalik

    2015-12-01

    Postoperative pain, swelling and trismus are the most common outcome after third molar surgery. Many methods have been tried to improve postoperative comfort after surgery. Ketamine is a phencyclidine derivative that induces a state of dissociative anesthesia. It is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and has a distinct suppression effect on central nervous system (CNS) sensitization. Ketamine in a subanesthetic dose is set to produce analgesic and anti-inflammatory effect. Sixty patients, between the age group of 18 and 38 years, undergoing the extraction of impacted mandibular third molar, reporting to the department of oral and maxillofacial surgery were included in the study. Patients were divided randomly into two groups: local anesthetic alone (LAA) and local anesthetic and ketamine (LAK). Statistical analysis was performed using the Mann-Whitney U/unpaired--t-test and Wilcoxon signed-rank test. There was a significant difference in mouth opening in the LAA and LAK group in the immediate postoperative period. There was a significant difference between the two groups after 1 hour (LAA: 2.37; LAK: 1.40), and 4 hours (LAA: 2.37; LAK: 1.40). There was a significant difference in terms of facial swelling in the immediate postoperative period and day 1 between the LAA and LAK group. Use of subanesthetic dose of ketamine is not only safe but also valuable in reducing patient morbidity after third molar surgery. Combination of a local anesthetic and subanesthetic dose of ketamine during surgical extraction of third molars provides good postoperative analgesia with less swelling and significantly less trismus.

  8. 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.

  9. Histamine H3 receptor antagonists display antischizophrenic activities in rats treated with MK-801.

    PubMed

    Mahmood, Danish; Akhtar, Mohd; Jahan, Kausar; Goswami, Dipanjan

    2016-09-01

    Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP. The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents.

  10. Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme.

    PubMed

    Siuciak, J A; McCarthy, S A; Chapin, D S; Reed, T M; Vorhees, C V; Repaske, D R

    2007-07-01

    PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.

  11. 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

  12. Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.

    PubMed

    Tillman, Tommy S; Alvarez, Frances J D; Reinert, Nathan J; Liu, Chuang; Wang, Dawei; Xu, Yan; Xiao, Kunhong; Zhang, Peijun; Tang, Pei

    2016-08-26

    Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors. Here we report the successful production of full-length wild type human α7nAChR from E. coli Chemically induced chaperones promote high expression levels of well-folded proteins. The choice of detergents, lipids, and ligands during purification determines the final protein quality. The purified α7nAChR not only forms pentamers as imaged by negative-stain electron microscopy, but also retains pharmacological characteristics of native α7nAChR, including binding to bungarotoxin and positive allosteric modulators specific to α7nAChR. Moreover, the purified α7nAChR injected into Xenopus oocytes can be activated by acetylcholine, choline, and nicotine, inhibited by the channel blockers QX-222 and phencyclidine, and potentiated by the α7nAChR specific modulators PNU-120596 and TQS. The successful generation of functional human α7nAChR from E. coli opens a new avenue for producing mammalian Cys-loop receptors to facilitate structure-based rational drug design. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Interaction of ibogaine with human α3β4-nicotinic acetylcholine receptors in different conformational states

    PubMed Central

    Arias, Hugo R.; Rosenberg, Avraham; Targowska-Duda, Katarzyna M.; Feuerbach, Dominik; Yuan, Xiao Juan; Jozwiak, Krzysztof; Moaddel, Ruin; Wainer, Irving W.

    2015-01-01

    The interaction of ibogaine and phencyclidine (PCP) with human (h) α3β4-nicotinic acetylcholine receptors (AChRs) in different conformational states was determined by functional and structural approaches including, radioligand binding assays, Ca2+ influx detections, and thermodynamic and kinetics measurements. The results established that (a) ibogaine inhibits (±)-epibatidine-induced Ca2+ influx in hα3β4 AChRs with ~9-fold higher potency than that for PCP, (b) [3H]ibogaine binds to a single site in the hα3β4 AChR ion channel with relatively high affinity (Kd = 0.46 ± 0.06 µM), and ibogaine inhibits [3H]ibogaine binding to the desensitized hα3β4 AChR with slightly higher affinity compared to the resting AChR. This is explained by a slower dissociation rate from the desensitized ion channel compared to the resting ion channel, and (c) PCP inhibits [3H]ibogaine binding to the hα3β4 AChR, suggesting overlapping sites. The experimental results correlate with the docking simulations suggesting that ibogaine and PCP interact with a binding domain located between the serine (position 6′) and valine/phenylalanine (position 13′) rings. This interaction is mediated mainly by van der Waals contacts, which is in agreement with the observed enthalpic contribution determined by non-linear chromatography. However, the calculated entropic contribution also indicates local conformational changes. Collectively our data suggest that ibogaine and PCP bind to overlapping sites located between the serine and valine/phenylalanine rings, to finally block the AChR ion channel, and in the case of ibogaine, to probably maintain the AChR in the desensitized state for longer time. PMID:20684041

  14. Interaction of ibogaine with human alpha3beta4-nicotinic acetylcholine receptors in different conformational states.

    PubMed

    Arias, Hugo R; Rosenberg, Avraham; Targowska-Duda, Katarzyna M; Feuerbach, Dominik; Yuan, Xiao Juan; Jozwiak, Krzysztof; Moaddel, Ruin; Wainer, Irving W

    2010-09-01

    The interaction of ibogaine and phencyclidine (PCP) with human (h) alpha3beta4-nicotinic acetylcholine receptors (AChRs) in different conformational states was determined by functional and structural approaches including, radioligand binding assays, Ca2+ influx detections, and thermodynamic and kinetics measurements. The results established that (a) ibogaine inhibits (+/-)-epibatidine-induced Ca2+ influx in h(alpha)3beta4 AChRs with approximately 9-fold higher potency than that for PCP, (b) [3H]ibogaine binds to a single site in the h(alpha)3beta4 AChR ion channel with relatively high affinity (Kd = 0.46 +/- 0.06 microM), and ibogaine inhibits [3H]ibogaine binding to the desensitized h(alpha)3beta4 AChR with slightly higher affinity compared to the resting AChR. This is explained by a slower dissociation rate from the desensitized ion channel compared to the resting ion channel, and (c) PCP inhibits [3H]ibogaine binding to the h(alpha)3beta4 AChR, suggesting overlapping sites. The experimental results correlate with the docking simulations suggesting that ibogaine and PCP interact with a binding domain located between the serine (position 6') and valine/phenylalanine (position 13') rings. This interaction is mediated mainly by van der Waals contacts, which is in agreement with the observed enthalpic contribution determined by non-linear chromatography. However, the calculated entropic contribution also indicates local conformational changes. Collectively our data suggest that ibogaine and PCP bind to overlapping sites located between the serine and valine/phenylalanine rings, to finally block the AChR ion channel, and in the case of ibogaine, to probably maintain the AChR in the desensitized state for longer time.

  15. F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (III) Activity in models of cognition and negative symptoms

    PubMed Central

    Depoortère, R; Auclair, A L; Bardin, L; Slot, L Bruins; Kleven, M S; Colpaert, F; Vacher, B; Newman-Tancredi, A

    2007-01-01

    Background and purpose: The D2/D3 receptor antagonist, D4 receptor partial agonist, and high efficacy 5-HT1A receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the ‘serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia. Experimental approach: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems. Key results: Through 5-HT1A activation, F15063 partially alleviated (MED: 0.04 mg kg−1) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg−1, F15063 reduced interaction by itself. F15063 (0.16 mg kg−1) selectively re-established PCP-impaired ‘cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04–0.63 mg kg−1) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D4 partial agonism, as it was blocked by the D4 antagonist L745,870. Finally, F15063 up to 40 mg kg−1 did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating. Conclusions and implications: The balance of D2/D3, D4 and 5-HT1A receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia. PMID:17375085

  16. Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review.

    PubMed

    Frank, D A; Augustyn, M; Knight, W G; Pell, T; Zuckerman, B

    2001-03-28

    Despite recent studies that failed to show catastrophic effects of prenatal cocaine exposure, popular attitudes and public policies still reflect the belief that cocaine is a uniquely dangerous teratogen. To critically review outcomes in early childhood after prenatal cocaine exposure in 5 domains: physical growth; cognition; language skills; motor skills; and behavior, attention, affect, and neurophysiology. Search of MEDLINE and Psychological Abstracts from 1984 to October 2000. Studies selected for detailed review (1) were published in a peer-reviewed English-language journal; (2) included a comparison group; (3) recruited samples prospectively in the perinatal period; (4) used masked assessment; and (5) did not include a substantial proportion of subjects exposed in utero to opiates, amphetamines, phencyclidine, or maternal human immunodeficiency virus infection. Thirty-six of 74 articles met criteria and were reviewed by 3 authors. Disagreements were resolved by consensus. After controlling for confounders, there was no consistent negative association between prenatal cocaine exposure and physical growth, developmental test scores, or receptive or expressive language. Less optimal motor scores have been found up to age 7 months but not thereafter, and may reflect heavy tobacco exposure. No independent cocaine effects have been shown on standardized parent and teacher reports of child behavior scored by accepted criteria. Experimental paradigms and novel statistical manipulations of standard instruments suggest an association between prenatal cocaine exposure and decreased attentiveness and emotional expressivity, as well as differences on neurophysiologic and attentional/affective findings. Among children aged 6 years or younger, there is no convincing evidence that prenatal cocaine exposure is associated with developmental toxic effects that are different in severity, scope, or kind from the sequelae of multiple other risk factors. Many findings once thought to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child's environment. Further replication is required of preliminary neurologic findings.

  17. To use or not to use: an update on licit and illicit ketamine use

    PubMed Central

    Li, Jih-Heng; Vicknasingam, Balasingam; Cheung, Yuet-Wah; Zhou, Wang; Nurhidayat, Adhi Wibowo; Jarlais, Don C Des; Schottenfeld, Richard

    2011-01-01

    Ketamine, a derivative of phencyclidine that was developed in the 1960s, is an anesthetic and analgesic with hallucinogenic effects. In this paper, the pharmacological and toxicological effects of ketamine are briefly reviewed. Ketamine possesses a wide safety margin but such a therapeutic benefit is somewhat offset by its emergence phenomenon (mind-body dissociation and delirium) and hallucinogenic effects. The increasing abuse of ketamine, initially predominantly in recreational scenes to experience a “k-hole” and other hallucinatory effects but more recently also as a drug abused during the workday or at home, has further pushed governments to confine its usage in many countries. Recently, urinary tract dysfunction has been associated with long-term ketamine use. In some long-term ketamine users, such damage can be irreversible and could result in renal failure and dialysis. Although ketamine has not yet been scheduled in the United Nations Conventions, previous studies using different assessment parameters to score the overall harms of drugs indicated that ketamine may cause more harm than some of the United Nations scheduled drugs. Some countries in Southeast and East Asia have reported an escalating situation of ketamine abuse. Dependence, lower urinary tract dysfunction, and sexual impulse or violence were the most notable among the ketamine-associated symptoms in these countries. These results implied that the danger of ketamine may have been underestimated previously. Therefore, the severity levels of the ketamine-associated problems should be scrutinized more carefully and objectively. To prevent ketamine from being improperly used and evolving into an epidemic, a thorough survey on the prevalence and characteristics of illicit ketamine use is imperative so that suitable policy and measures can be taken. On the other hand, recent findings that ketamine could be useful for treating major depressive disorder has given this old drug a new impetus. If ketamine is indeed a remedy for treating depression, more research on the risks and benefits of its clinical use will be indispensable. PMID:24474851

  18. Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

    PubMed Central

    Colestock, Tristan; Morris, Hamilton; Bortolotto, Zuner A.; Lodge, David; Halberstadt, Adam L.; Brandt, Simon D.

    2016-01-01

    1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine. PMID:27314670

  19. Vaccines against drugs of abuse: a viable treatment option?

    PubMed

    Kantak, Kathleen M

    2003-01-01

    Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a means of eliminating illicit drug use as well as drug overdose and neurotoxicity. Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and nicotine are now in clinical trials because they can offer long-term protection with minimal treatment compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are currently under development. An underlying theme in this research is the need for high concentrations of circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is repeatedly available, especially in high doses. Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks that need to be considered. These include: a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice;a lack of an effect on drug craving that predisposes an addict to relapse; and tremendous individual variability in antibody formation. Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal and ethical concerns. All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the medical treatment of drug abuse will not be radically different from treatment of other chronic diseases.

  20. Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats

    PubMed Central

    Ahnaou, Abdallah; Biermans, Ria; Drinkenburg, Wilhelmus H.

    2016-01-01

    Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not. PMID:26808689

  1. Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

    PubMed Central

    Lee, Anna M; Miksys, Sharon; Tyndale, Rachel F

    2006-01-01

    CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban®, a smoking cessation drug), activate tobacco-smoke nitrosamines, and inactivate nicotine. Hepatic CYP2B6 is induced by phenobarbital and induction may affect in vivo nicotine disposition, while brain CYP2B6 induction may affect local levels of centrally acting substrates. We investigated the effect of chronic phenobarbital treatment on induction of in vivo nicotine disposition and CYP2B6 expression in the liver and brain of African Green (Vervet) monkeys. Monkeys were split into two groups (n=6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg−1 phenobarbital. Monkeys were given a 0.1 mg kg−1 nicotine dose subcutaneously before and after treatment. Phenobarbital treatment resulted in a significant, 56%, decrease (P=0.04) in the maximum nicotine plasma concentration and a 46% decrease (P=0.003) in the area under the concentration–time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (P<0.05) of CYP2B6 protein levels was observed in all regions tested (caudate, putamen, hippocampus, cerebellum, brain stem and frontal cortex) ranging from 2-fold to 150-fold. CYP2B6 expression was induced in specific cells, such as frontal cortical pyramidal cells and thalamic neurons. In conclusion, chronic phenobarbital treatment in monkeys resulted in increased in vivo nicotine disposition, and induced hepatic and brain CYP2B6 protein levels and cellular expression. This induction may alter the metabolism of CYP2B6 substrates including peripherally acting drugs such as cyclophosphamide and centrally acting drugs such as bupropion, ecstasy and phencyclidine. PMID:16751792

  2. Assessment of the ion-trap mass spectrometer for routine qualitative and quantitative analysis of drugs of abuse extracted from urine.

    PubMed

    Vorce, S P; Sklerov, J H; Kalasinsky, K S

    2000-10-01

    The ion-trap mass spectrometer (MS) has been available as a detector for gas chromatography (GC) for nearly two decades. However, it still occupies a minor role in forensic toxicology drug-testing laboratories. Quadrupole MS instruments make up the majority of GC detectors used in drug confirmation. This work addresses the use of these two MS detectors, comparing the ion ratio precision and quantitative accuracy for the analysis of different classes of abused drugs extracted from urine. Urine specimens were prepared at five concentrations each for amphetamine (AMP), methamphetamine (METH), benzoylecgonine (BZE), delta9-carboxy-tetrahydrocannabinol (delta9-THCCOOH), phencyclidine (PCP), morphine (MOR), codeine (COD), and 6-acetylmorphine (6-AM). Concentration ranges for AMP, METH, BZE, delta9-THCCOOH, PCP, MOR, COD, and 6-AM were 50-2500, 50-5000, 15-800, 1.5-65, 1-250, 500-32000, 250-21000, and 1.5-118 ng/mL, respectively. Sample extracts were injected into a GC-quadrupole MS operating in selected ion monitoring (SIM) mode and a GC-ion-trap MS operating in either selected ion storage (SIS) or full scan (FS) mode. Precision was assessed by the evaluation of five ion ratios for n = 15 injections at each concentration using a single-point calibration. Precision measurements for SIM ion ratios provided coefficients of variation (CV) between 2.6 and 9.8% for all drugs. By comparison, the SIS and FS data yielded CV ranges of 4.0-12.8% and 4.0-11.2%, respectively. The total ion ratio failure rates were 0.2% (SIM), 0.7% (SIS), and 1.2% (FS) for the eight drugs analyzed. Overall, the SIS mode produced stable, comparable mean ratios over the concentration ranges examined, but had greater variance within batch runs. Examination of postmortem and quality-control samples produced forensically accurate quantitation by SIS when compared to SIM. Furthermore, sensitivity of FS was equivalent to SIM for all compounds examined except for 6-AM.

  3. Growth, Development, and Behavior in Early Childhood Following Prenatal Cocaine Exposure

    PubMed Central

    Frank, Deborah A.; Augustyn, Marilyn; Knight, Wanda Grant; Pell, Tripler; Zuckerman, Barry

    2008-01-01

    Context Despite recent studies that failed to show catastrophic effects of prenatal cocaine exposure, popular attitudes and public policies still reflect the belief that cocaine is a uniquely dangerous teratogen. Objective To critically review outcomes in early childhood after prenatal cocaine exposure in 5 domains: physical growth; cognition; language skills; motor skills; and behavior, attention, affect, and neurophysiology. Data Sources Search of MEDLINE and Psychological Abstracts from 1984 to October 2000. Study Selection Studies selected for detailed review (1) were published in a peerreviewed English-language journal; (2) included a comparison group; (3) recruited samples prospectively in the perinatal period; (4) used masked assessment; and (5) did not include a substantial proportion of subjects exposed in utero to opiates, amphetamines, phencyclidine, or maternal human immunodeficiency virus infection. Data Extraction Thirty-six of 74 articles met criteria and were reviewed by 3 authors. Disagreements were resolved by consensus. Data Synthesis After controlling for confounders, there was no consistent negative association between prenatal cocaine exposure and physical growth, developmental test scores, or receptive or expressive language. Less optimal motor scores have been found up to age 7 months but not thereafter, and may reflect heavy tobacco exposure. No independent cocaine effects have been shown on standardized parent and teacher reports of child behavior scored by accepted criteria. Experimental paradigms and novel statistical manipulations of standard instruments suggest an association between prenatal cocaine exposure and decreased attentiveness and emotional expressivity, as well as differences on neurophysiologic and attentional/affective findings. Conclusions Among children aged 6 years or younger, there is no convincing evidence that prenatal cocaine exposure is associated with developmental toxic effects that are different in severity, scope, or kind from the sequelae of multiple other risk factors. Many findings once thought to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child’s environment. Further replication is required of preliminary neurologic findings. PMID:11268270

  4. Contextual and behavioral control of antipsychotic sensitization induced by haloperidol and olanzapine.

    PubMed

    Zhang, Chen; Li, Ming

    2012-02-01

    Repeated administration of haloperidol (HAL) and olanzapine (OLZ) causes a progressively enhanced disruption of the conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or the PCP (3.2 mg/kg, subcutaneously) hyperlocomotion model under HAL or OLZ for 5 consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated HAL or OLZ treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with HAL or OLZ did not show a stronger inhibition of CAR-induced or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may develop an association with unconditional drug effects through a Pavlovian conditioning process. They may also serve as occasion setters to modulate the expression of sensitized responses. As antipsychotic sensitization mimics the clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic.

  5. Contextual and behavioral control of antipsychotic sensitization induced by haloperidol and olanzapine

    PubMed Central

    Zhang, Chen; Li, Ming

    2011-01-01

    Repeated administration of haloperidol and olanzapine causes a progressively enhanced disruption of conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined to the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or PCP (3.2 mg/kg, sc) hyperlocomotion model under haloperidol or olanzapine for five consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated haloperidol or olanzapine treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with haloperidol or olanzapine did not show a stronger inhibition of CAR or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may enter an association with unconditional drug effects via a Pavlovian conditioning process. They may also serve as occasion-setters to modulate the expression of sensitized responses. Because antipsychotic sensitization mimics clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic. PMID:22157143

  6. 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

  7. Cooperative interaction among the various regulatory sites within the NMDA receptor-channel complex in modulating the evoked responses to noxious thermal stimuli of spinal dorsal horn neurons in the cat.

    PubMed

    Song, X J; Zhao, Z Q

    1998-05-01

    Interactions among antagonists acting at different regulatory sites within the N-methyl-D-aspartate (NMDA) receptor-channel complex on the evoked responses to noxious thermal stimuli of wide dynamic range (WDR) neurons in spinal dorsal horn were studied on 21 adult anesthetized and spinalized cats. The responses of nociceptive spinal dorsal horn neurons to noxious heating (45-55 degrees C) of the glabrous skin of the unilateral hind paw were reduced markedly by iontophoretically applied antagonists. The specific recognition site antagonist, DL-2-amino-5-phosphonovaleratic acid (APV), the strychnine-insensitive glycine site antagonist 7-chlorokynurenic acid (7CKA), the polyamine site antagonist ifenprodil (IFEN), and the phencyclidine (PCP) site antagonists ketamine (KET) and MK-801 (40-100 nA) significantly reduced (t-tests, P < 0.01) the noxious thermal stimulus-evoked responses in about 70% of the neurons by (mean +/- SE) 54.1 +/- 5.8% (n = 19), 80.8 +/- 4.7% (n = 16), 51.1 +/- 6.4% (n = 10), 77 +/- 4.9% (n = 16) and 81.2 +/- 8.1% (n = 5), respectively. APV and IFEN were less effective in blocking noxious thermal stimuli-evoked responses than 7CKA, KET and MK-801 (ANOVA, P < 0.05). The responses were completely inhibited in some neurons. After co-administration of the antagonists, APV + 7CKA, APV + IFEN, 7CKA + IFEN, APV + KET and APV + MK-801, all at the subthreshold ejection current, the responses were reduced markedly in 13 of 16, 7 of 10, 5 of 10, 3 of 6 and 3 of 5 neurons, respectively. The present study suggests that blockage of any component of the NMDA receptor-channel complex antagonizes the NMDA receptor-mediated response, and that there are the cooperative interactions among the various regulatory sites within the NMDA receptor-channel complex in the transmission or modulation of spinal nociceptive thermal information.

  8. Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase

    PubMed Central

    Carroll, Marilyn E.; Kohl, Emily A.; Johnson, Krista M.; LaNasa, Rachel M.

    2013-01-01

    Background In previous studies with male and female rhesus monkeys withdrawal of access to oral phencyclidine (PCP) self administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer. Impulsive choice for SACC increased during PCP withdrawal more than females. Objectives The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle. Materials and methods In Component 1 PCP and water were available from 2 drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In Component 2 a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or 6 delayed SACC deliveries, and the delay was increased by 1 sec after a response on the delayed lever and decreased by 1 sec after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP-withdrawal, that occurred during the mid-folllicular phase (Days 7–11) or the late-luteal (Days 24–28) phase of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases. Results PCP deliveries were higher during the luteal vs the follicular phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration. Conclusions PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys. PMID:23344553

  9. The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development

    PubMed Central

    Keavy, Deborah; Bristow, Linda J.; Sivarao, Digavalli V.; Batchelder, Margaret; King, Dalton; Thangathirupathy, Srinivasan; Macor, John E.; Weed, Michael R.

    2016-01-01

    The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans. PMID:27035340

  10. Expression, subcellular localization and regulation of sigma receptor in retinal Müller cells

    PubMed Central

    Jiang, Guoliang; Mysona, Barbara; Dun, Ying; Gnana-Prakasam, Jaya P.; Pabla, Navjotsin; Li, Weiguo; Dong, Zheng; Ganapathy, Vadivel; Smith, Sylvia B.

    2013-01-01

    Purpose Sigma receptors (σR) are non-opioid, non-phencyclidine binding sites with robust neuroprotective properties. σR1 is expressed in brain oligodendrocytes, but its expression and binding capacity have not been analyzed in retinal glial cells. This study examined the expression, subcellular localization, binding activity and regulation of σR1 in retinal Müller cells. Methods Primary mouse Müller cells (1°MC) were analyzed by RT-PCR, immunoblotting and immunocytochemistry for the expression of σR1 and data were compared to the rat Müller cell line, rMC-1 and rat ganglion cell line, RGC-5. Confocal microscopy was used to determine the subcellular σR1 location in 1°MC. Membranes prepared from these cells were used for binding assays using [3H]-pentazocine (PTZ). The kinetics of binding, the ability of various σR1 ligands to compete with σR1 binding and the effects of nitric oxide (NO) and reactive oxygen species (ROS) donors on binding were examined. Results σR1 is expressed in 1°MC and is localized to the nuclear and endoplasmic reticulum membranes. Binding assays showed that in 1°MCs, rMC-1 and RGC-5 cells, the binding of PTZ was saturable. [3H]-PTZ bound with high affinity in RGC-5 and rMC-1 cells and the binding was similarly robust in 1°MC. Competition studies showed marked inhibition of [3H]-PTZ binding in the presence of σR1-specific ligands. Incubation of cells with NO and ROS donors markedly increased σR1 binding activity. Conclusions Müller cells express σR1 and demonstrate robust σR1 binding activity, which is inhibited by σR1 ligands and is stimulated during oxidative stress. The potential of Müller cells to bind σR1 ligands may prove beneficial in retinal degenerative diseases such as diabetic retinopathy. PMID:17122151

  11. Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality.

    PubMed

    Heresco-Levy, Uriel

    2003-10-01

    The neurotransmission mediated by the excitatory amino acids (EAA) glutamate (GLU) and aspartate is of interest to the pharmacotherapy of psychosis due to its role in neurodevelopment and neurotoxicity, its complex interactions with dopaminergic and other neurotransmitter systems and its pivotal importance in recent models of schizophrenia. Accumulating evidence indicates that modulation of glutamatergic neurotransmission may play an important role in the mechanisms of action of atypical antipsychotic drugs. The principles of the phencyclidine (PCP) model of schizophrenia suggest that conventional neuroleptics cannot counteract all aspects of schizophrenia symptomatology, while a more favorable outcome, including anti-negative and cognitive symptoms effects, would be expected with the use of treatment modalities targeting glutamatergic neurotransmission. Clozapine and other presently used atypical antipsychotics differ from conventional neuroleptics in the way they affect various aspects of glutamatergic receptors function. In this context, a specific hypothesis suggesting an agonistic role of clozapine at the N-methyl-D-aspartate (NMDA) subtype of GLU receptors has been postulated. Furthermore, the results of the first generation of clinical trials with glycine (GLY) site agonists of the NMDA receptor in schizophrenia suggest that this type of compounds (1) have efficacy and side effects profiles different than those of conventional neuroleptics and (2) differ in their synergic effects when used in addition to conventional neuroleptics versus clozapine and possibly additional atypical antipsychotics. These findings (1) bring further support to the hypothesis that glutamatergic effects may play an important role in the mechanism of action of atypical antipsychotics, (2) help explain the unique clinical profile of clozapine, and (3) suggest that GLY site agonists of the NMDA receptor may represent a new class of atypical antipsychotic medication. Future research in this area is bound to bring about a better understanding of the role of glutamatergic neurotransmission manipulation in the pharmacotherapy of psychosis and the development of novel pharmacological strategies targeting GLU brain systems.

  12. 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.

  13. Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia.

    PubMed

    Nakashima, Masato; Imada, Haruka; Shiraishi, Eri; Ito, Yuki; Suzuki, Noriko; Miyamoto, Maki; Taniguchi, Takahiko; Iwashita, Hiroki

    2018-04-01

    The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, ( N -{(1 S )-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3- b ]pyrazine-4(1 H )-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  14. The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia

    PubMed Central

    Bristow, Linda J.; Easton, Amy E.; Li, Yu-Wen; Sivarao, Digavalli V.; Lidge, Regina; Jones, Kelli M.; Post-Munson, Debra; Daly, Christopher; Lodge, Nicholas J.; Gallagher, Lizbeth; Molski, Thaddeus; Pieschl, Richard; Chen, Ping; Hendricson, Adam; Westphal, Ryan; Cook, James; Iwuagwu, Christiana; Morgan, Daniel; Benitex, Yulia; King, Dalton; Macor, John E.; Zaczek, Robert; Olson, Richard

    2016-01-01

    The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1–10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1–10 mg/kg, sc) and set shift performance in rats (1–10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1–3 mg/kg, po). BMS-933043 also improved auditory gating (0.56–3 mg/kg, sc) and mismatch negativity (0.03–3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans. PMID:27467081

  15. Ethanolic extracts of Alstonia Scholaris and Bacopa Monniera possess neuroleptic activity due to anti-dopaminergic effect

    PubMed Central

    Jash, Rajiv; Chowdary, K. Appana

    2014-01-01

    Background: An increased inclination has been observed for the use of herbal drugs in chronic and incurable diseases. Treatment of psychiatric diseases like schizophrenia is largely palliative and more importantly, a prominent adverse effect prevails with the majority of anti-psychotic drugs, which are the extrapyramidal motor disorders. Existing anti-psychotic drug therapy is not so promising, and their adverse effect is a matter of concern for continuing the therapy for long duration. Objective: This experimental study was done to evaluate the neuroleptic activity of the ethanolic extracts of two plants Alstonia Scholaris and Bacopa Monnieri with different anti-psychotic animal models with a view that these plant extracts shall have no or at least reduced adverse effect so that it can be used for long duration. Materials and Methods: Two doses of both the extracts (100 and 200 mg/kg) and also standard drug haloperidol (0.2 mg/kg) were administered to their respective groups once daily with 5 different animal models. After that, the concentration of the dopamine neurotransmitter was estimated in two different regions of the brain viz. frontal cortex and striatum. Results: The result of the study indicated a significant reduction of amphetamine-induced stereotype and conditioned avoidance response for both the extracts compared with the control group, but both did not have any significant effect in phencyclidine-induced locomotor activity and social interaction activity. However, both the extracts showed minor signs of catalepsy compared to the control group. The study also revealed that the neuroleptic effect was due to the reduction of the dopamine concentration in the frontal cortex region of the rat brain. The results largely pointed out the fact that both the extract may be having the property to alleviate the positive symptoms of schizophrenia by reducing the dopamine levels of dopaminergic neurons of the brain. Conclusion: The estimation of dopamine in the two major regions of brain indicated the alteration of dopamine levels was the reason for the anti-psychotic activity as demonstrated by the different animal models. PMID:24497742

  16. Hair-based rapid analyses for multiple drugs in forensics and doping: application of dynamic multiple reaction monitoring with LC-MS/MS.

    PubMed

    Shah, Iltaf; Petroczi, Andrea; Uvacsek, Martina; Ránky, Márta; Naughton, Declan P

    2014-01-01

    Considerable efforts are being extended to develop more effective methods to detect drugs in forensic science for applications such as preventing doping in sport. The aim of this study was to develop a sensitive and accurate method for analytes of forensic and toxicological nature in human hair at sub-pg levels. The hair test covers a range of different classes of drugs and metabolites of forensic and toxicological nature including selected anabolic steroids, cocaine, amphetamines, cannabinoids, opiates, bronchodilators, phencyclidine and ketamine. For extraction purposes, the hair samples were decontaminated using dichloromethane, ground and treated with 1 M sodium hydroxide and neutralised with hydrochloric acid and phosphate buffer and the homogenate was later extracted with hexane using liquid-liquid extraction (LLE). Following extraction from hair samples, drug-screening employed liquid chromatography coupled to tandem mass spectrometric (LC-MS/MS) analysis using dynamic multiple reaction monitoring (DYN-MRM) method using proprietary software. The screening method (for > 200 drugs/metabolites) was calibrated with a tailored drug mixture and was validated for 20 selected drugs for this study. Using standard additions to hair sample extracts, validation was in line with FDA guidance. A Zorbax Eclipse plus C18 (2.1 mm internal diameter × 100 mm length × 1.8 μm particle size) column was used for analysis. Total instrument run time was 8 minutes with no noted matrix interferences. The LOD of compounds ranged between 0.05-0.5 pg/mg of hair. 233 human hair samples were screened using this new method and samples were confirmed positive for 20 different drugs, mainly steroids and drugs of abuse. This is the first report of the application of this proprietary system to investigate the presence of drugs in human hair samples. The method is selective, sensitive and robust for the screening and confirmation of multiple drugs in a single analysis and has potential as a very useful tool for the analysis of large array of controlled substances and drugs of abuse.

  17. 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.

  18. Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip.

    PubMed

    Dauth, Stephanie; Maoz, Ben M; Sheehy, Sean P; Hemphill, Matthew A; Murty, Tara; Macedonia, Mary Kate; Greer, Angie M; Budnik, Bogdan; Parker, Kevin Kit

    2017-03-01

    Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiology, potential neurotoxic effects of chemicals, and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell composition, protein expression, metabolism, and electrical activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and observed a reduction of overall firing activity, as well as altered amounts of astrocytes and specific neuronal cell types compared with separately cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas separately while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features. NEW & NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections. Copyright © 2017 the American Physiological Society.

  19. Interactions between recreational drugs and antiretroviral agents.

    PubMed

    Antoniou, Tony; Tseng, Alice Lin-In

    2002-10-01

    To summarize existing data regarding potential interactions between recreational drugs and drugs commonly used in the management of HIV-positive patients. Information was obtained via a MEDLINE search (1966-August 2002) using the MeSH headings human immunodeficiency virus, drug interactions, cytochrome P450, medication names commonly prescribed for the management of HIV and related opportunistic infections, and names of commonly used recreational drugs. Abstracts of national and international conferences, review articles, textbooks, and references of all articles were also reviewed. Literature on pharmacokinetic interactions was considered for inclusion. Pertinent information was selected and summarized for discussion. In the absence of specific data, prediction of potential clinically significant interactions was based on pharmacokinetic and pharmacodynamic properties. All protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of the cytochrome P450 system. Many classes of recreational drugs, including benzodiazepines, amphetamines, and opioids, are also metabolized by the liver and can potentially interact with antiretrovirals. Controlled interaction studies are often not available, but clinically significant interactions have been observed in a number of case reports. Overdoses secondary to interactions between the "rave" drugs methylenedioxymethamphetamine (MDMA) or gamma-hydroxybutyrate (GHB) and PIs have been reported. PIs, particularly ritonavir, may also inhibit metabolism of amphetamines, ketamine, lysergic acid diethylmide (LSD), and phencyclidine (PCP). Case series and pharmacokinetic studies suggest that nevirapine and efavirenz induce methadone metabolism, which may lead to symptoms of opiate withdrawal. A similar interaction may exist between methadone and the PIs ritonavir and nelfinavir, although the data are less consistent. Opiate metabolism can be inhibited or induced by concomitant PIs, and patients should be monitored for signs of toxicity and/or loss of analgesia. PIs should not be coadministered with midazolam and triazolam, since prolonged sedation may occur. Interactions between agents commonly prescribed for patients with HIV and recreational drugs can occur, and may be associated with serious clinical consequences. Clinicians should encourage open dialog with their patients on this topic, to avoid compromising antiretroviral efficacy and increasing the risk of drug toxicity.

  20. Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip

    PubMed Central

    Dauth, Stephanie; Maoz, Ben M.; Sheehy, Sean P.; Hemphill, Matthew A.; Murty, Tara; Macedonia, Mary Kate; Greer, Angie M.; Budnik, Bogdan

    2017-01-01

    Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiology, potential neurotoxic effects of chemicals, and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell composition, protein expression, metabolism, and electrical activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and observed a reduction of overall firing activity, as well as altered amounts of astrocytes and specific neuronal cell types compared with separately cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas separately while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features. NEW & NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections. PMID:28031399

  1. Patterns of Drugs and Drug Metabolites Observed in Meconium: What Do They Mean?

    PubMed

    McMillin, Gwendolyn A; Wood, Kelly E; Strathmann, Frederick G; Krasowski, Matthew D

    2015-10-01

    Meconium drug testing is performed to detect potentially harmful drug exposures in a newborn. Interpretation of meconium drug testing results can be complicated based on the patterns and proportional concentrations of the drug(s) and/or drug metabolite(s) detected. The objective of this study was to analyze meconium drug testing patterns in a de-identified dataset from a national reference laboratory (n = 76,631) and in a subset of the data, wherein specimens originated at a single academic medical center for which detailed chart review was possible (n = 3635). Meconium testing was performed using 11 immunoassay-based drug screens. Specimens that were positive for one or more drug screens were reflexed to corresponding confirmation tests performed by gas chromatography or liquid chromatography with mass spectrometric detection, targeted to identify and quantitate specific parent drug(s) and metabolite(s). The positivity rate was the highest for the cannabis metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (25.2%, n = 18,643), followed by opiates/oxycodone (23.2%, n = 17,778), amphetamine/methamphetamine (6.7%, n = 5134), cocaine metabolites (5.5%, n = 4205), methadone (5.3%, n = 4093), benzodiazepines (3.4%, n = 2603), barbiturates (1.1%, n = 834), propoxyphene (1.0%, n = 749), and phencyclidine (0.1%, n = 44). Based on documented pharmacy history, drugs administered to either the mother or newborn during the birth hospitalization were detected in meconium, providing evidence that drugs can be incorporated into meconium rapidly. Drugs administered directly to the newborn after birth were recovered in meconium as both parent drug and metabolites, providing evidence of neonatal metabolism. Overall, patterns observed in meconium exhibited many similarities to those patterns commonly reported with urine drug testing. Interpretation of meconium drug testing results requires comparison of results with clinical and analytical expectations, including maternal admissions to drug use, pharmacy history, recognized metabolic patterns for drugs of interest, cutoff concentrations, and other performance characteristics of the test. Concentrations of drug(s) and drug metabolites(s) may not reliably predict timing of drug use, extent of drug use, or frequency of drug exposures.

  2. Legal highs: staying on top of the flood of novel psychoactive substances

    PubMed Central

    Baumeister, David; Tojo, Luis M.

    2015-01-01

    There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called ‘legal highs’, which are more appropriately called new or novel psychoactive substances (NPS). A cat-and-mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their ‘parent’ compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the ‘parent’ compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called ‘psychonauts’ consuming NPS will also need informed ‘psychotherapeutonauts’. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future. PMID:26240749

  3. Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population

    PubMed Central

    Iwayama, Yoshimi; Yamamoto, Naoki; Toyota, Tomoko; Suzuki, Katsuaki; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Kurumaji, Akeo; Yoshikawa, Takeo

    2018-01-01

    Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia. PMID:29309433

  4. Immobilization of free-ranging male pacific walruses (Odobenus rosmarus divergens) with carfentanil citrate and naltrexone hydrochloride

    USGS Publications Warehouse

    Mulcahy, Daniel M.; Tuomi, P.A.; Garner, Gerald W.; Jay, Chadwick V.

    2003-01-01

    The major challenges in immobilization of free-ranging walruses (Odobenus rosmarus divergens) are to produce a deep level of anesthesia very quickly (to avoid darted animals from entering the water and drowning), and to find a drug or drug combination that requires only a small volume to be delivered by dart, is safe, reversible, and that provides an adequate period of immobilization to permit attachment of instruments, phlebotomy, and measuring. Tiletamine-zolazepam is recommended for immobilization of pinnipeds, with inhalant anesthesia recommended for more extensive procedures requiring better analgesia (Gales 1989). Drugs that have been used on free-ranging walruses include ketamine (Hagenbeck et al. 1975), phencyclidine combined with acepromazine (DeMaster et al. 1981), etorphine (Born and Knutsen 1990, Hills 1992, Griffiths et al. 1993), tiletamine-zolazepam (Stirling and Sjare 1988, Griffiths et al. 1993), medetomidine and ketamine (Lydersen et al. 1992), and carfentanil (Hills 1992, Lanthier et al. 1999). Carfentanil but not etorphine is presently licensed and available in the United States.Forty-eight adult male walruses were immobilized with carfentanil citrate in the summers of 1995-1997 at Maggy Beach (58°57’N, 161°76’W), a land haul-out located at Cape Peirce within the Togiak National Wildlife Refuge in southwest Alaska. The number of animals present during immobilizations ranged from three to several thousand. Criteria for choosing individual walruses included good body condition, the presence of two tusks of sufficient diameter for the attachment of radio transmitters, and presence of the animal at the edge of the herd. In addition, we chose animals that were resting quietly and which had not recently hauled out (as judged by skin color). Walruses were darted from ranges of approximately 10-15 m using a Cap-Chur rifle (Palmer Chemical and Equipment Co., Douglasville, Georgia, GA 30133). Carfentanil citrate (Wildlife Pharmaceuticals, Fort Collins, CO 80524) was administered by dart with a 10-cm needle to the lumbar region. Most animals received a dose of 2.7 or 3.0 mg of carfentanil. One animal received a second dose after the first syringe apparently burst on impact. Induction times were measured as being the time at which the animal collapsed, failed to respond to external stimuli, or as the time when the darter stood up and moved towards the animal.

  5. Recent national trends in Salvia divinorum use and substance-use disorders among recent and former Salvia divinorum users compared with nonusers

    PubMed Central

    Wu, Li-Tzy; Woody, George E; Yang, Chongming; Li, Jih-Heng; Blazer, Dan G

    2011-01-01

    Context Media and scientific reports have indicated an increase in recreational use of Salvia divinorum. Epidemiological data are lacking on the trends, prevalence, and correlates of S. divinorum use in large representative samples, as well as the extent of substance use and mental health problems among S. divinorum users. Objective To examine the national trend in prevalence of S. divinorum use and to identify sociodemographic, behavioral, mental health, and substance-use profiles of recent (past-year) and former users of S. divinorum. Design Analyses of public-use data files from the 2006–2008 United States National Surveys on Drug Use and Health (N = 166,453). Setting Noninstitutionalized individuals aged 12 years or older were interviewed in their places of residence. Main measures Substance use, S. divinorum, self-reported substance use disorders, criminality, depression, and mental health treatment were assessed by standardized survey questions administered by the audio computer-assisted self-interviewing method. Results Among survey respondents, lifetime prevalence of S. divinorum use had increased from 0.7% in 2006 to 1.3% in 2008 (an 83% increase). S. divinorum use was associated with ages 18–25 years, male gender, white or multiple race, residence of large metropolitan areas, arrests for criminal activities, and depression. S. divinorum use was particularly common among recent drug users, including users of lysergic acid diethylamide (53.7%), ecstasy (30.1%), heroin (24.2%), phencyclidine (22.4%), and cocaine (17.5%). Adjusted multinomial logistic analyses indicated polydrug use as the strongest determinant for recent and former S. divinorum use. An estimated 43.0% of past-year S. divinorum users and 28.9% of former S. divinorum users had an illicit or nonmedical drug-use disorder compared with 2.5% of nonusers. Adjusted logistic regression analyses showed that recent and former S. divinorum users had greater odds of having past-year depression and a substance-use disorder (alcohol or drugs) than past-year alcohol or drug users who did not use S. divinorum. Conclusion S. divinorum use is prevalent among recent or active drug users who have used other hallucinogens or stimulants. The high prevalence of substance use disorders among recent S. divinorum users emphasizes the need to study health risks of drug interactions. PMID:21709724

  6. The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors.

    PubMed

    Riga, Maurizio S; Bortolozzi, Analia; Campa, Letizia; Artigas, Francesc; Celada, Pau

    2016-02-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. The effects of psychotomimetics and psychomotor stimulants on two schedules promoting response switching in the rat.

    PubMed

    Evenden, John

    2002-10-01

    Psychosis and psychotomimetic drugs result in a disorganisation of the structure of thought and behaviour. Normalising these is one of the objects of antipsychotic therapy, and methods for predicting such a therapeutic effect would be of value. The effects of a number of psychotomimetic agents were examined on the way in which rats distributed responding over two response levers using two different procedures, to assay their effects on behavioural organisation. Previously, amphetamine has been found to increase response switching using these schedules. In the first, the random reinforcement procedure, one of the two levers was selected at random as "correct", and responses on this lever were reinforced with food under a random ratio schedule. No signal was given to distinguish the levers. Responding could also result in the food tray being illuminated, but no food pellet was delivered ("no-food" event). Responses on the second lever ("incorrect") had no programmed consequences. After each food delivery or "no-food" event the levers designated as "correct" and "incorrect" were reassigned at random, and the rat had to open the food tray to restart the schedule. In the second procedure, the rats were required to make 21 responses before a switch between the two levers resulted in food delivery [Fixed Ratio (FR) 21-switch]. The responses making up the FR could be distributed freely between the two levers. Phencyclidine (PCP), scopolamine, caffeine and ethanol increased switching under the random reinforcement procedure, but (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and atropine did not. PCP, caffeine, lysergic acid diethylamide (LSD) and atropine increased switching under the FR21-switch procedure, but ethanol did not. The increases in switching produced by PCP, LSD and the anticholinergics were accompanied by marked reductions in response rate, whereas those produced by amphetamine and caffeine were not. The effects of amphetamine, and PCP were strongly dependent on the baseline probability of switching, those of atropine and caffeine moderately so, and those of LSD and ethanol only weakly so. Of the agents tested, psychomotor stimulants appear to produce the most selective increases in switching. The procedures described here may be useful for assaying the disorganisation of behaviour produced by other psychotomimetics and may have value in the detection of novel antipsychotic drugs.

  8. In Vivo Pharmacological Evaluations of Novel Olanzapine Analogues in Rats: A Potential New Avenue for the Treatment of Schizophrenia

    PubMed Central

    Jafari, Somayeh; Huang, Xu-Feng; Andrews, Jessica L.; Fernandez-Enright, Francesca

    2013-01-01

    Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis. PMID:24349027

  9. Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor

    PubMed Central

    Olmos, Gabriel; DeGregorio-Rocasolano, Nuria; Regalado, M Paz; Gasull, Teresa; Boronat, M Assumpció; Trullas, Ramón; Villarroel, Alvaro; Lerma, Juan; García-Sevilla, Jesús A

    1999-01-01

    This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells.Exposure (30 min) of energy deprived cells to L-glutamate (1–100 μM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 μM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine).Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 μM (EC100) L-glutamate with the rank order (EC50 in μM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole] (101)>RX821002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors.Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding.In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10–12 μM at 0 mV.It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamate-induced necrotic neuronal cell death in vitro and that this effect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore. PMID:10455281

  10. Trends in laboratory test volumes for Medicare Part B reimbursements, 2000-2010.

    PubMed

    Shahangian, Shahram; Alspach, Todd D; Astles, J Rex; Yesupriya, Ajay; Dettwyler, William K

    2014-02-01

    Changes in reimbursements for clinical laboratory testing may help us assess the effect of various variables, such as testing recommendations, market forces, changes in testing technology, and changes in clinical or laboratory practices, and provide information that can influence health care and public health policy decisions. To date, however, there has been no report, to our knowledge, of longitudinal trends in national laboratory test use. To evaluate Medicare Part B-reimbursed volumes of selected laboratory tests per 10,000 enrollees from 2000 through 2010. Laboratory test reimbursement volumes per 10,000 enrollees in Medicare Part B were obtained from the Centers for Medicare & Medicaid Services (Baltimore, Maryland). The ratio of the most recent (2010) reimbursed test volume per 10,000 Medicare enrollees, divided by the oldest data (usually 2000) during this decade, called the volume ratio, was used to measure trends in test reimbursement. Laboratory tests with a reimbursement claim frequency of at least 10 per 10,000 Medicare enrollees in 2010 were selected, provided there was more than a 50% change in test reimbursement volume during the 2000-2010 decade. We combined the reimbursed test volumes for the few tests that were listed under more than one code in the Current Procedural Terminology (American Medical Association, Chicago, Illinois). A 2-sided Poisson regression, adjusted for potential overdispersion, was used to determine P values for the trend; trends were considered significant at P < .05. Tests with the greatest decrease in reimbursement volumes were electrolytes, digoxin, carbamazepine, phenytoin, and lithium, with volume ratios ranging from 0.27 to 0.64 (P < .001). Tests with the greatest increase in reimbursement volumes were meprobamate, opiates, methadone, phencyclidine, amphetamines, cocaine, and vitamin D, with volume ratios ranging from 83 to 1510 (P < .001). Although reimbursement volumes increased for most of the selected tests, other tests exhibited statistically significant downward trends in annual reimbursement volumes. The observed changes in reimbursement volumes may be explained by disease prevalence and severity, patterns of drug use, clinical or laboratory practices, and testing recommendations and guidelines, among others. These data may be useful to policy makers, health systems researchers, laboratory directors, and industry scientists to understand, address, and anticipate trends in laboratory testing in the Medicare population.

  11. Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands.

    PubMed

    de Costa, B R; Bowen, W D; Hellewell, S B; George, C; Rothman, R B; Reid, A A; Walker, J M; Jacobson, A E; Rice, K C

    1989-08-01

    The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 [(+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de [(+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol [(+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-[N- [(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)SULP], and [3H]-1- [1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM [[3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa ([3H]BREM) and 1270 +/- 168 nM at sigma [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors [[3H]-(+)-3-PPP] and 250 +/- 8 nM ([3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)

  12. Motor and Cognitive Outcomes Through Three Years Of Age In Children Exposed To Prenatal Methamphetamine

    PubMed Central

    Smith, Lynne M.; LaGasse, Linda L.; Derauf, Chris; Newman, Elana; Shah, Rizwan; Haning, William; Arria, Amelia; Huestis, Marilyn; Strauss, Arthur; Grotta, Sheri Della; Dansereau, Lynne M.; Lin, Hai; Lester, Barry M.

    2010-01-01

    Background Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown. Objective To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age. Design/Methods IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self-report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n= 330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n= 331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time. Results Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P = 0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age. Conclusions There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years. PMID:21256431

  13. Motor and cognitive outcomes through three years of age in children exposed to prenatal methamphetamine.

    PubMed

    Smith, Lynne M; LaGasse, Linda L; Derauf, Chris; Newman, Elana; Shah, Rizwan; Haning, William; Arria, Amelia; Huestis, Marilyn; Strauss, Arthur; Della Grotta, Sheri; Dansereau, Lynne M; Lin, Hai; Lester, Barry M

    2011-01-01

    Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown. To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age. IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, and type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n=330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n=331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time. Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P=0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age. There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. Inquiries into the Biological Significance of Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8 Through Investigations of TARP γ-8 Null Mice§.

    PubMed

    Gleason, Scott D; Kato, Akihiko; Bui, Hai H; Thompson, Linda K; Valli, Sabrina N; Stutz, Patrick V; Kuo, Ming-Shang; Falcone, Julie F; Anderson, Wesley H; Li, Xia; Witkin, Jeffrey M

    2015-01-01

    Transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein (TARP) γ-8 is an auxiliary protein associated with some AMPA receptors. Most strikingly, AMPA receptors associated with this TARP have a relatively high localization in the hippocampus. TARP γ-8 also modifies the pharmacology and trafficking of AMPA receptors. However, to date there is little understanding of the biological significance of this auxiliary protein. In the present set of studies we provide a characterization of the differential pharmacology and behavioral consequences of deletion of TARP γ-8 by comparing the wild type (WT) and γ-8 -/- (knock-out, KO) mouse. KO mice were mildly hyperactive in a locomotor arena but not in other environments compared to WT mice. Additionally, the KO mice demonstrated enhanced locomotor stimulatory effects of both d-amphetamine and phencyclidine. Marble-burying and digging behaviors were dramatically reduced in KO mice. In another assay that can detect anxiety-like phenotypes, the elevated plus maze, no differences were observed in overall movement or open arm entries. In the forced-swim assay, KO mice displayed decreases in immobility time like the antidepressant imipramine and the AMPA receptor potentiator, LY392098. In KO mice, the antidepressant-like effects of LY392098 were prevented whereas the effects of imipramine were unaffected. Convulsions were induced by pentylenetetrazole, N-methyl-D-aspartate, and by kainic acid. However, in KO mice, kainic acid produced less tonic convulsions and lethality. KO mice had reduced levels of norepinephrine in hippocampus and cerebellum but not in hypothalamus or prefrontal cortex, decreased levels of cAMP in hippocampus, and increased levels of acetylcholine in the hypothalamus and prefrontal cortex. KO mice displayed decreased turnover of dopamine and increased histamine turnover in multiple brain areas In contrast, serotonin and its metabolites were not significantly affected by deletion of the γ-8 protein. Of a large panel of plasma lipids, only two monoacylglycerols (1OG and 2OG) were marginally but nonsignificantly altered in WT vs KO mice. Overall, the data suggest genetic inactivation of this specific population of AMPA receptors results in modest changes in behavior characterized by a mild hyperactivity which is condition dependent and a marked reduction in digging and burying behaviors. Despite deletion of TARP γ-8, chemoconvulsants were still active. Consistent with their predicted pharmacological actions, the convulsant effects of kainate and the antidepressant-like effects of an AMPA receptor potentiator (both acting upon AMPA receptors) were reduced or absent in KO mice.

  15. [Use of Emerging Drugs in Medellín, Colombia].

    PubMed

    Castaño Pérez, Guillermo A; Calderón Vallejo, Gustavo A; Berbesi Fernández, Dedsy Yajaira

    2013-09-01

    The ongoing emergence of new synthetic substances that are used as drugs is a constant challenge to public health. Emerging drugs is the concept used in this research project to define the emergence of new psychoactive substances at a given time, a specific context and group, the reemergence of others that some epidemiologists considered had lost their prevalence, and the sudden prevalence of drugs that had low levels of consumption. This research project was carried out using an empirical-analytical approach using a mixed methods study. The convenience sample was made up of 510 drug dependents institutionalized in treatment centers in Medellin in the year 2011. The examination was carried out related to the consumption of emerging drugs. An ad hoc tool was applied to all the drug users in order to identify which of the drugs of this study they considered to be emergent. Once the consumers were identified and selected based on the frequency of consumption, and the prevalence in the last year and last month, a semi-structured interview was carried out to find out details on the substances and their consumption characteristics. Based on the new drug consumers in Medellin, 82.2% were male and 17.8% female. As regards education levels, 58.2% were in high school, 26.8% hold higher technical or college degrees, and 1.4% had no schooling. Only 27.8% held a steady job, occasional employment, or were independent business owners, 40.7% were students and 8.9% were housewives. More than three-quarters (76.3%) were single, and 17.8% had a steady partner. The sample represented all social classes. Of all the emerging drugs found in this study, the prevalence of benzodiazepines stands out (flunitrazepam and clonazepam), life prevalence (LP), 97.5%; last year prevalence (LYP), 67.9%, and last month prevalence (LMP), 46.7%. These were followed by the synthetic drugs (LSD, Ecstasies, amphetamines, GHB, Vegetable Ecstasies, Phencyclidine; Methamphetamine, Ketamine, 2CB), with LP, 96.5%; LYP, 44.5%, and LMP, 23.5%. Then there was smokable cocaine (Crack and Free-Base), with LP, 80%, LYP, 52.1%, and LYP=31.7%. The opiate derivatives (heroine, morphine, opium, codeine, dextromethorphan, meperidine, fentanyl) had an LP, 61.4%; LYP, 26.7% and LMP, 16%. The consumption statistics of the hallucinogens such as mushrooms, scopolamine and "yague", had an LP, 73.5%; LYP, 23.2% and LMP, 12.2%. Finally, use of inhalants such as popper and dichloromethane (Dick) had an LP, 87.9%; LYP, 37.6% and LMP, 21.6%. These results are an alert to the need to track the development of these so called emergent drugs due to the risks they pose for public health. Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  16. Prevention of Excitotoxicity in Primary Retinal Ganglion Cells by (+)-Pentazocine, a Sigma Receptor-1-Specific Ligand

    PubMed Central

    Dun, Ying; Thangaraju, Muthusamy; Prasad, Puttur; Ganapathy, Vadivel; Smith, Sylvia B.

    2013-01-01

    Purpose σRs are non-opioid, non-phencyclidine binding sites with robust neuroprotective properties. Previously, we induced death in the RGC-5 cell line using very high concentrations (1 mM) of the excitatory amino acids glutamate (Glu) and homocysteine (Hcy) and demonstrated that the σR1 ligand (+)-pentazocine ((+)-PTZ) could protect against cell death. The purpose of the present study was to establish a physiologically relevant paradigm for testing the neuroprotective effect of (+)-PTZ in retinal ganglion cells. Methods Primary ganglion cells (1°GCs) were isolated by immunopanning from retinas of 1-day-old mice, maintained in culture for 3 days and then exposed to 10, 20, 25 or 50 µM Glu or 10, 25, 50 or 100 µM Hcy for 6 or 18 h in the presence or absence of (+)-PTZ (0.5, 1, 3 µM). Cell viability was measured using the Live/Dead and ApopTag Fluorescein In Situ Assays. Expression of σR1 was assessed by immunocytochemistry, RT-PCR and western blotting. Morphological appearance of live ganglion cells and their processes was examined over time (0, 3, 6, 18 h) by differential interference contrast (DIC) microscopy following exposure to excitotoxins in the presence or absence of (+)-PTZ. Results 1°GCs showed robust σR1 expression. The cells are exquisitely sensitive to Glu or Hcy toxicity (6 h treatment with 25 or 50 µM Glu or 50 or 100 µM Hcy induced marked cell death). 1°GCs pre-treated 1 h with (+)-PTZ followed by 18 h co-treatment with 25 µM Glu and (+)-PTZ showed a marked decrease in cell death: (25 µM Glu alone: 50%; 25 µM Glu/0.5 µM (+)-PTZ: 38%; 25 µM Glu/1 µM (+)-PTZ: 20%; 25 µM Glu/3 µM (+)-PTZ: 18%). Similar results were obtained with Hcy. σR1 mRNA and protein levels did not change in the presence of the excitotoxins. DIC examination of cells exposed to excitotoxins revealed substantial disruption of neuronal processes; co-treatment with (+)-PTZ revealed marked preservation of these processes. The stereoselective effect of (+)-PTZ for σR1 was established in experiments in which (−)-PTZ, the levo-isomer form of pentazocine, had no neuroprotective effect on excitotoxin-induced ganglion cell death. Conclusions 1°GCs express σR1; their marked sensitivity to Glu and Hcy toxicity mimics the sensitivity observed in vivo, making them a highly relevant model for testing neuroprotection. Pre-treatment of cells with 1–3 µM (+)-PTZ, but not (−)-PTZ affords significant protection against Glu- and Hcy-induced cell death. σR1 ligands may be very useful therapeutic agents in retinal diseases in which ganglion cells die. PMID:17898305

  17. Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

    PubMed Central

    Sershen, Henry; Hashim, Audrey; Dunlop, David S.; Suckow, Raymond F.; Cooper, Tom B.; Javitt, Daniel C.

    2016-01-01

    Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be determined, overall it supports continued glutamatergic drug development. PMID:26857796

  18. The Toxicology Investigators Consortium Case Registry--the 2012 experience.

    PubMed

    Wiegand, Timothy; Wax, Paul; Smith, Eric; Hart, Katherine; Brent, Jeffrey

    2013-12-01

    In 2010, the American College of Medical Toxicology (ACMT) established its Case Registry, the Toxicology Investigators Consortium (ToxIC). All cases are entered prospectively and include only suspected and confirmed toxic exposures cared for at the bedside by board-certified or board-eligible medical toxicologists at its participating sites. The primary aims of establishing this Registry include the development of a realtime toxico-surveillance system in order to identify and describe current or evolving trends in poisoning and to develop a research tool in toxicology. ToxIC allows for extraction of data from medical records from multiple sites across a national and international network. All cases seen by medical toxicologists at participating institutions were entered into the database. Information characterizing patients entered in 2012 was tabulated and data from the previous years including 2010 and 2011 were included so that cumulative numbers and trends could be described as well. The current report includes data through December 31st, 2012. During 2012, 38 sites with 68 specific institutions contributed a total of 7,269 cases to the Registry. The total number of cases entered into the Registry at the end of 2012 was 17,681. Emergency departments remained the most common source of consultation in 2012, accounting for 61 % of cases. The most common reason for consultation was for pharmaceutical overdose, which occurred in 52 % of patients including intentional (41 %) and unintentional (11 %) exposures. The most common classes of agents were sedative-hypnotics (1,422 entries in 13 % of cases) non-opioid analgesics (1,295 entries in 12 % of cases), opioids (1,086 entries in 10 % of cases) and antidepressants (1,039 entries in 10 % of cases). N-acetylcysteine (NAC) was the most common antidote administered in 2012, as it was in previous years, followed by the opioid antagonist naloxone, sodium bicarbonate, physostigmine and flumazenil. Anti-crotalid Fab fragments were administered in 109 cases or 82 % of cases in which a snake envenomation occurred. There were 57 deaths reported in the Registry in 2012. The most common associated agent alone or in combination was the non-opioid analgesic acetaminophen, being reported in 10 different cases. Other common agents and agent classes involved in death cases included ethanol, opioids, the anti-diabetic agent metformin, sedatives-hypnotics and cardiovascular agents, in particular amlodipine. There were significant trends identified during 2012. Abuse of over-the-counter medications such as dextromethorphan remains prevalent. Cases involving dextromethorphan continued to be reported at frequencies higher than other commonly abused drugs including many stimulants, phencyclidine, synthetic cannabinoids and designer amphetamines such as bath salts. And, while cases involving synthetic cannabinoids and psychoactive bath salts remained relatively constant from 2011 to 2012 several designer amphetamines and novel psychoactive substances were first reported in the Registry in 2012 including the NBOME compounds or "N-bomb" agents. LSD cases also spiked dramatically in 2012 with an 18-fold increase from 2011 although many of these cases are thought to be ultra-potent designer amphetamines misrepresented as "synthetic" LSD. The 2012 Registry included over 400 Adverse Drug Reactions (ADRs) involving 4 % of all Registry cases with 106 agents causing at least 2 ADRs. Additional data including supportive cares, decontamination, and chelating agent use are also included in the 2012 annual report. The Registry remains a valuable toxico-surveillance and research tool. The ToxIC Registry is a unique tool for identifying and characterizing confirmed cases of significant or potential toxicity or complexity to require bedside care by a medical toxicologist.

  19. Optimization and application of an extraction procedure to determine drugs of abuse in solid environmental matrices of Turia River Basin

    NASA Astrophysics Data System (ADS)

    Andres, Maria Jesus; Alvarez, Rodrigo; Andreu, Vicente; Pico, Yolanda

    2015-04-01

    After their consumption, drug of abuse are excreted through urine or faeces, as parent compound or as secondary metabolites that arrive to wastewater treatment plants. Accordingly, the incomplete removal of these compounds in the treatment plants could release them into environmental compartments [1]. This scenario needs attention from an ecotoxicological perspective because their possible negative effects [2]. The aim of this study is to optimize and apply a solvent extraction and solid phase clean-up methodology to obtain a valid procedure for the extraction of these compounds in different solid matrices. Amphetamine, methamphetamine, ethylamphetamine, ecstasy, ethylone, bk-MMBDB and MBDB belong to phenylethylamine group; codeine and ketamine belong to opioid and phencyclidine group, respectively, and benzoylecgonine is the major excreted metabolite of the alkaloid cocaine. To optimize the method to determinate drugs of abuse in environmental solid matrices, two replicates and one blank were prepared for each sample of sediment. They were prepared by adding 1 g of sediment sample, 5 mL of buffer (methanol-Mc Ilvaine 50:50) and internal standard to obtain a final concentration in the extract of 25 ng/g. Also standards of drugs of abuse were added to the replicates to obtain a final concentration of 100 ng/g. Then all samples were shaken, sonicated and centrifuged and the supernatant was separated and placed in a 250 mL volumetric flask, which was filled the rest with distilled water. SPE was carried out with Strata-X cartridges and 250 mL of sample were passed through them. The extracts were eluted with 6 mL of methanol, evaporated to dryness and reconstituted in 1 mL of methanol-water 1:9. One of the replicates was filtrated through 0.22 μm pore size and the others were not. The samples were determined by liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS/MS) using an electrospray ionization source (ESI) in positive ionization mode. The results show that extraction recoveries of phenylethylamine group were from 39.3 to 92.4%. For codeine and ketamine, the recoveries ranged from 44.4 to 90.6% and from 61.3 to 79.5%, respectively. Benzoylecgonine presented recoveries ranged from 72 to 77.5%. The precision of the method was below 20% for all the compounds. The method was applied to determine these drugs of abuse in sediments of the Turia River Basin. Ecstasy, codeine, ketamine and benzoylecgonine were found at concentrations ranging from 0.22 ng/g to 25 ng/g in 6 sampling points. Very limited information exists on the presence of drugs of abuse in environmental matrices. Nothing can be concluded about the differences between the recoveries obtained in unfiltered and filtered samples because they do not follow any trend. These results confirm the reliability of the method as well as its suitability to be applied in environmental studies. Acknowledgements This work has been supported by the Spanish Ministry of Economy and Competitiveness trough the project SCARCE-CDS 2009-0065, CGL 2011-29703-C02-01 and CGL 2011-29703-C02-02. MJ Andrés Costa also acknowledges to this Ministry the FPI grant to perform her PhD. References [1] T.H. Boles, M.J.M. Wells, Analysis of amphetamine and methamphetamine as emerging pollutants in wastewater and wastewater-impacted streams, Journal of Chromatography A 1217 (2010) 2561. [2] C. Postigo, M.J. López de Alda, D. Barceló, Drugs of abuse and their metabolites in the Ebro River basin: Occurrence in sewage and surface water, sewage treatment plants removal efficiency, and collective drug usage estimation Environment International 36 (2010) 75.

Some links on this page may take you to non-federal websites. Their policies may differ from this site.
Top