Information to Users

Total Page:16

File Type:pdf, Size:1020Kb

Information to Users INFORMATION TO USERS This manuscript MS been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, sorne thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction la dependent upon the quality of the copy submitted. Broken or indistinct prim. coIored or poor quality illustrations and photographs, print bleedlhrough, substandard margins. and improper alignment can adversely affect reproduction. ln the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicat8 the deletion. Cversize materials (e.g., maps, drawings. charts) are reproduced by sectioning the original, beginning at the upper Ieft-hand corner and continuing from left to right in equal sections with small overlaps. Photographs incluclect in the original manuscript have been reproduced xerographically in this copy. Higher quality 8- x 9'" black and white photographie pnnts are available for any photographs or illustrations appearing in this copy for an additional charge. Contad UMI directly to order. Bell & Howell Information and Leaming 300 North Zeeb Road, Ann Arbor, MI 48108-1346 USA 800-521-0600 ELECTROPHYSIOLOGICAL STUDIES IN RAT DORSAL BIPPOCAMPUS: MODULATION OF THE NEURONAL RESPONSE TO N-METHYL-D-ASPAIlTATE DY SELECTIVE SIGMA. AND SIGMAz LIGANDS BY Sophie Couture Student number: 9549733 JuIy 1998 A thesis submitted to the Faculty ofGraduate Studies and Research in partial fulfilment ofthe degree of Master in Science Sophie COUTURE. 1998 McGill University Department of neurology and neurosurgery MontréaJ7 Québec National Library Bibliothèque nationale 1+1 of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. rue Wellington Ottawa ON K1 A 0N4 0IIawa ON K1A 0N4 Canada Canada The author has granted a non­ L'auteur a accordé une licence non exclusive licence aUowing the exclusive permettant à la National Library ofCanada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seU reproduire, prêter, distribuer ou copies ofthis thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownersbip ofthe L'auteur conserve la propriété du copyright in tbis thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts from it Ni la thèse ni des extraits substantiels may he printed or otherwise de ceUe·ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son penmSSlon. autorisation. 0-612-50743-2 Canad~ ACKNOWLEDGEMENTS • These experiments were carried oui: in the Neurobiological Psychiatrie Unit at McGill under the supervision of Dr. Guy Debonnel. The research was conducted to fu1f1l the requirements of a Ma~ter in Science. 1 wish to thank Dr. Debonnel for his expert advice and his support and guidance throughout my studies. 1would also like to thank the members of the selection committee. namely Or. de Montigny. Dr. Debonnel and Dr. Blier for accepting rny candidacy as a graduate student and. providing me with such a stimulating environment. 1 am also grateful to Claude Bouchard. Normand Lavoie and Yves Simard for always being available for technical assistance and advice. A special "thanks" to aIl staff members and fellow graduate students for their continuous support and encouragement during my studies at McGill University. Finally, 1 would like to covey a very special thank you to my friend and fiance. Patrice for his encouragement and patients and, my parents for their understanding and continuous support. • Manuscripts and authorship Guidelilles for Thesis Preparation • Faculty ofGraduate Studies and Research~ McGill University The review of the literature and the studies presented in this Master thesis concem the modulation of the neuronal response by selective sigma ligands. Two experimental series are presented in tbis thesis. One article has been published, the second one has been submitted. 1have conducted all the experimental work, analyzed the data, drew the figures and written the papers. In regards to the second article~ the technician Nonnand Lavoie also contributed to a minor extent in the obtention ofexperimental datas. It is the policy ofthe Faculty at McGill University to allow the students to include as chapters "original publications" concerning the thesis research project. The faculty regulations Can he summarized as follows: Candidates have the option~ subject to the approval of their Department. of including. as part oftheir thesis. copies ofthe text ofa paper(s) submitted for publication. or the clearly-duplicated text of published paper(s), provided that these copies are bound as an integral part of the thesis. [fthis option is chosen. connecting texis, providing 10gicaJ bridges between the different papers. are mandatory. • II The thesis must still conform to aIl other requirements of the "Guidelines Conceming Thesis • Preparation" and should he in a literary form that is more than a mere collection of manuscripts published or to he published. The thesis must include, as separate chapters or sections: (1) a table of contents, (2) a general abstract in English and French, (3) an introduction which clearly states the rationaie and objectives of the study. (4) a comprehensive review of the background literature to the subject of the thesis, when this review is appropriate, (5) a final overall conclusion and/or summary. Additional rnaterial (procedural and design data, as weIl as descriptions of equipments used) must he provided where appropriate and in sufficient detail Ce.g. in appendices) to allow a clear and precise judgemem to be made of the importance and originality of the research reported in the thesis. • III LIST OF PUBLICATIONS • Published Abstracts 1. Debonnel G, and Couture S (1997) Modulation of the neuronal response to N-Methyl-D- Aspartate by selective O 2 ligands, Neuroscience Meeting. New Orleans. 2. Couture S, and Debonnel G (1997) Sensitivity ofselective 0 ligands to the opiate antagonist naloxone, Neuroscience Meeting, New Orleans. 3. Couture S, and Debonnel G (1996) Modulation of the neuronal response to N-Methyl-D- Aspartate by selective O 2 Ligands. ACNP abstract. 4. Couture S, and Debonnel G (1996) Modulation of the neuronal response to N-Methyl-D- Aspartate by selective O 2 Ligands, Research Day, Dept. of Psychiatry. Mcgill University. 5. Couture S. and Debonnel G (1997) Sensitivity ofselective (J ligands to the opiate antagonist naloxone, Research Day, Dept.ofNeurology, McGill University. 6. Couture S, and Debonnel G (l997) Sensitivity of selective (J ligands to the opiate antagonist naloxone, Research Day, Dept. of Psychiatry. 7. Couture S, and Debonnel G (1997) Implication of (J ligands as potential anticonvulsants or proconvulsants, Symposium on Epilepsy, Laurentides. Published Articles 1. Couture S, and Debonnel G (1998) Modulation of the neuronal response to N-Methyl-D- aspartate by selective (J2Iigands, SYNAPSE, 29:62-71. • IV ., Couture S, Lavoie N, and Debonnel G (1998) Suppression of {+)-pentazocine effects by • naloxone (submitted, SYNAPSE). • v ABSTRACT • 1t has now been accepted for severa! years, that (] receptors exist as at least two distinct entities denoted a 1 and O 2, We have previously shown in our laboratory that several selective (] 1 ligands potentiate the neuronal response to NMDA in the dorsal hippocampus of rat. The non selective 0/01 ligand, DTG, aIso potentiates the neuronal response. However. when il is administered at doses between 3 and 40 Jlglkg, the increase of NMDA-induced activation tums in to an epileptoid activity. Data presented in tbis thesis suggest that similarly to (] 1 ligands, selective 02 ligands such as Lu 28-179. Lu 29-252 and BD 1008 dose-dependently potentiate the NMDA response. Interestingly, the effects of these drugs are not reversed by the non selective (] /02 antagonist haloperidoI. by the neurosteroid progesterone nor by the selective (J 1 antagonist NE-l00. The (] 2 ligand CB-64D a1so potentiates. dose-dependently. the NMDA response, its effect. however is reversed by haloperidol and by the neurosteroid progesterone. AlI O 2 ligands failed to generate any epileptoid activity on their own but, with the subsequent administration of a (11 agonist (10-1784). an epileptoid activity was induced. This epileptoid activity was not observed following the subsequent administration of the al agonist (+)-pentazocine. The a receptor is believed to be a non opioid receptor insensitive to naloxone. However. recently, a protein has been identified that resembles the cr opioid receptor originally proposed by Martin and colleagues in 1976. Therefore to answer this discrepancy, we verified the spectrum of (] ligands for which the potentiation of the NMDA response is mediated by the naloxone-sensitive (] receptor. The potentiation ofthe NMDA response induced by (+)-pentazocine. but not 10-1784. BD- • • 737 and L. 687-384. was suppressed by naloxone. The data presented in tbis thesis suggest that: (1) similarly to CJ 1 ligands. CJ 2 agonists potentiate the NMDA response; (2) the coactivation ofone type of CJ 1 and O 2 receptors appears to he necessary to induce epileptoid activity; (3) haloperidol may not act as a O 2 antagonist; (4) and (+)-pentazocine might act on two types of 01 receptor: one which is haloperidol sensitive and an other, which is naIoxone sensitive but different than the opiate receptors. • 2 ABRÉGÉ • On reconnaît maintenant l'existence d'au moins deux sous types de récepteurs 0: les récepteurs 0 1 et cr1. Plusieurs études de notre laboratoire ont démontré que de nombreux ligands a ( potentialisent la réponse neuronale au NMDA dans l'hippocampe dorsal du rat. n a également été démontré que le DTG~ un ligand non sélectif a ( /oz, potentialise aussi la réponse neuronale au NMDA mais que~ lorsque il est administré à des doses comprises entre 3 et 40 flglkg, il induit une activité épiIepto·.oe.
Recommended publications
  • Ie-O-JY -CH2 S (56) References Cited Wherein N Is 0 to 6, X" and Y Are Independently H, Cl, F, CH, CH, CH, CH, OCH, OH, CF, OCF, NO, U.S
    US005574060A United States Patent (19) 11) Patent Number: 5,574,060 Rothman et al. (45) Date of Patent: Nov. 12, 1996 54 SELECTIVE INHIBITORS OF BIOGENIC "Hydrindene Derivatives as Potential Oral Hypoglycemic AMINE TRANSPORTERS Agents: N-Alkyl 1,2,3,3a,4,8b-Hexahydroindeno1,2-b) pyrroles', De et al., Journal of Pharmaceutical Sciences, vol. (75) Inventors: Richard Rothman, Silver Spring, Md.; 62, No. 8, Aug. 1973, pp. 1363-1364. Frank J. Carroll, Durham, N.C.; Bruce Blough, Raleigh, N.C.; Samuel (List continued on next page.) W. Mascarella, Hillsborough, N.C. Primary Examiner-Mark L. Berch (73) Assignees: The United States of America as Attorney, Agent, or Firm-Morgan & Finnegan LLP represented by the Department of 57) ABSTRACT Health and Human Services, Washington, D.C.; Office of Technology The present invention provides a compound having the Transfer, Bethesda, Md.; Research Structure: Triangle Institue, Research Triangle Park, N.C. (21) Appl. No.: 203,222 22 Filed: Feb. 28, 1994 Related U.S. Application Data H 63 Continuation-in-part of Ser. No. 105,747, Aug. 12, 1993, abandoned. wherein X, Y, and Z are independently H, Cl, Br, F, OCH, I, or an alkyl group having 1 to 6 carbon atoms; and R is (51) Int. Cl." .......................... A61K 31/40; A61K 31/47; C07D 403/06; C07D 471/08 X (52) U.S. Cl. ............................ 514/411; 546/94; 546/146; 54.6/150; 548/427: 548/428 58) Field of Search .............................. 548/427; 514/411 -ie-O-JY -CH2 S (56) References Cited wherein n is 0 to 6, X" and Y are independently H, Cl, F, CH, CH, CH, CH, OCH, OH, CF, OCF, NO, U.S.
    [Show full text]
  • Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type?
    REVIEW published: 21 November 2019 doi: 10.3389/fpsyt.2019.00835 Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type? Alexei M. Bygrave 1, Kasyoka Kilonzo 2, Dimitri M. Kullmann 3, David M. Bannerman 4 and Dennis Kätzel 2* 1 Department of Neuroscience, Johns Hopkins University, Baltimore, MD, United States, 2 Institute of Applied Physiology, Ulm University, Ulm, Germany, 3 UCL Queen Square Institute of Neurology, University College London, London, United Kingdom, 4 Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom Hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs), whether caused by endogenous factors like auto-antibodies or mutations, or by pharmacological or genetic manipulations, produces a wide variety of deficits which overlap with—but do not precisely match—the symptom spectrum of schizophrenia. In order to understand how NMDAR hypofunction leads to different components of the syndrome, it is necessary to take into account which neuronal subtypes are particularly affected by it in terms of detrimental Edited by: functional alterations. We provide a comprehensive overview detailing findings in rodent Bernat Kocsis, Harvard Medical School, models with cell type–specific knockout of NMDARs. Regarding inhibitory cortical cells, United States an emerging model suggests that NMDAR hypofunction in parvalbumin (PV) positive Reviewed by: interneurons is a potential risk factor for this disease. PV interneurons display a selective Margarita Behrens, Salk Institute for Biological Studies, vulnerability resulting from a combination of genetic, cellular, and environmental factors United States that produce pathological multi-level positive feedback loops. Central to this are two Vasileios Kafetzopoulos, antioxidant mechanisms—NMDAR activity and perineuronal nets—which are themselves Harvard Medical School, United States impaired by oxidative stress, amplifying disinhibition.
    [Show full text]
  • Cerebellar Toxicity of Phencyclidine
    The Journal of Neuroscience, March 1995, 75(3): 2097-2108 Cerebellar Toxicity of Phencyclidine Riitta N&kki, Jari Koistinaho, Frank Ft. Sharp, and Stephen M. Sagar Department of Neurology, University of California, and Veterans Affairs Medical Center, San Francisco, California 94121 Phencyclidine (PCP), clizocilpine maleate (MK801), and oth- Phencyclidine (PCP), dizocilpine maleate (MK801), and other er NMDA antagonists are toxic to neurons in the posterior NMDA receptor antagonistshave attracted increasing attention cingulate and retrosplenial cortex. To determine if addition- becauseof their therapeutic potential. These drugs have neuro- al neurons are damaged, the distribution of microglial ac- protective properties in animal studies of focal brain ischemia, tivation and 70 kDa heat shock protein (HSP70) induction where excitotoxicity is proposedto be an important mechanism was studied following the administration of PCP and of neuronal cell death (Dalkara et al., 1990; Martinez-Arizala et MK801 to rats. PCP (10-50 mg/kg) induced microglial ac- al., 1990). Moreover, NMDA antagonists decrease neuronal tivation and neuronal HSP70 mRNA and protein expression damage and dysfunction in other pathological conditions, in- in the posterior cingulate and retrosplenial cortex. In ad- cluding hypoglycemia (Nellgard and Wieloch, 1992) and pro- dition, coronal sections of the cerebellar vermis of PCP (50 longed seizures(Church and Lodge, 1990; Faingold et al., 1993). mg/kg) treated rats contained vertical stripes of activated However, NMDA antagonists are toxic to certain neuronal microglial in the molecular layer. In the sagittal plane, the populations in the brain. Olney et al. (1989) demonstratedthat microglial activation occurred in irregularly shaped patch- the noncompetitive NMDA antagonists,PCP, MK801, and ke- es, suggesting damage to Purkinje cells.
    [Show full text]
  • Supplementary Materials
    Supplementary Materials Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state Running title: Effects of mu-opioid receptor agonism in Wistar-Kyoto rats Mehnaz I Ferdousi1,3,4, Patricia Calcagno1,2,3,4, Morgane Clarke1,2,3,4, Sonali Aggarwal1,2,3,4, Connie Sanchez5, Karen L Smith5, David J Eyerman5, John P Kelly1,3,4, Michelle Roche2,3,4, David P Finn1,3,4,* 1Pharmacology and Therapeutics, 2Physiology, School of Medicine, 3Centre for Pain Research and 4Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland. 5Alkermes Inc., Waltham, Massachusetts, USA. *Corresponding author: Professor David P Finn, Pharmacology and Therapeutics, School of Medicine, Human Biology Building, National University of Ireland Galway, University Road, Galway, H91 W5P7, Ireland. Tel: +353 (0)91 495280 E-mail: [email protected] S.1. Supplementary methods S.1.1. Elevated plus maze test The elevated plus maze (EPM) test assessed the effects of drug treatment on anxiety-related behaviours in WKY and SD rats. The wooden arena, which was elevated 50 cm above the floor, consisted of central platform (10x10 cm) connecting four arms (50x10 cm each) in the shape of a “plus”. Two arms were enclosed by walls (30 cm high, 25 lux) and the other two arms were without any enclosure (60 lux). On the test day, 5 min after the HPT, rats were removed from the home cage, placed in the centre zone of the maze with their heads facing an open arm, and the behaviours were recorded for 5 min with a video camera positioned on top of the arena.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun
    USOO9687445B2 (12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun. 27, 2017 (54) ORAL FILM CONTAINING OPIATE (56) References Cited ENTERC-RELEASE BEADS U.S. PATENT DOCUMENTS (75) Inventor: Michael Hsin Chwen Li, Warren, NJ 7,871,645 B2 1/2011 Hall et al. (US) 2010/0285.130 A1* 11/2010 Sanghvi ........................ 424/484 2011 0033541 A1 2/2011 Myers et al. 2011/0195989 A1* 8, 2011 Rudnic et al. ................ 514,282 (73) Assignee: LTS Lohmann Therapie-Systeme AG, Andernach (DE) FOREIGN PATENT DOCUMENTS CN 101703,777 A 2, 2001 (*) Notice: Subject to any disclaimer, the term of this DE 10 2006 O27 796 A1 12/2007 patent is extended or adjusted under 35 WO WOOO,32255 A1 6, 2000 U.S.C. 154(b) by 338 days. WO WO O1/378O8 A1 5, 2001 WO WO 2007 144080 A2 12/2007 (21) Appl. No.: 13/445,716 (Continued) OTHER PUBLICATIONS (22) Filed: Apr. 12, 2012 Pharmaceutics, edited by Cui Fude, the fifth edition, People's Medical Publishing House, Feb. 29, 2004, pp. 156-157. (65) Prior Publication Data Primary Examiner — Bethany Barham US 2013/0273.162 A1 Oct. 17, 2013 Assistant Examiner — Barbara Frazier (74) Attorney, Agent, or Firm — ProPat, L.L.C. (51) Int. Cl. (57) ABSTRACT A6 IK 9/00 (2006.01) A control release and abuse-resistant opiate drug delivery A6 IK 47/38 (2006.01) oral wafer or edible oral film dosage to treat pain and A6 IK 47/32 (2006.01) substance abuse is provided.
    [Show full text]
  • RTI-4793-14, a New Ligand with High Affinity and Selectivity For
    SYNAPSE 16:59-65 (1994) RTI-4793-14, a New Ligand With High Affinity and Selectivity for the ( +)-MK801-Insensitive [3H]1 -[ 1 -( 2- thienyl)cyclohexyl]piperidine Binding Site (PCP Site 2) of Guinea Pig Brain CARL B. GOODMAN, D. NIGEL THOMAS, AGU PERT, BETSEY EMILIEN, JEAN L. CADET, F. IVY CARROLL, BRUCE E. BLOUGH, S. WAYNE MASCARELLA, MICHAEL A. ROGAWSKI, SWAMINATHAN SUBRAMANIAM, AM) RICHARD B. ROTHMAN Clinical Psychopharmacology Section, NIDMNIH Addiction Research Center, Baltimore, Maryland 21224 (C.B.G., B.E., J.L.C., R.B.R.); Biological Psychiatry Branch, NZMH (D.N.T., A.P.) and Neuronal Excitability Section, Epilepsy Research Branch, NINDS (M.A.R., S.S.), NIH, Bethesda, Maryland 20892; and Chemistry and Life Sciences, Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194 (F.I.C., B.E.B., S.W.M.) KEY WORDS Phencyclidine receptor, RTI-4793-14, PCP, Biogenic amine reuptake carrier, ( + )-MK801, Guinea pig brain ABSTRACT L3HlTCP, an analog of the dissociative anesthetic phencyclidine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one that is MK-801 sensitive and one that is not. The MK-801-sensitive site (PCP site 1) is associated with NMDA receptors, whereas the MK-801-insensitive site (PCP site 2) may be associated with biogenic amine transporters (BAT).Although several “BAT ligands” are known that bind selectively to PCP site 2 and not to PCP site 1 (such as indatraline), these corn- pounds have low affinity for site 2 (K, values > 1 pM). Here we demonstrate that the novel pyrrole RTI-4793-14 is a selective, high affinity ligand for PCP site 2.
    [Show full text]
  • Cannabinoid Transmission in the Prelimbic Cortex Bidirectionally
    15642 • The Journal of Neuroscience, September 25, 2013 • 33(39):15642–15651 Behavioral/Cognitive Cannabinoid Transmission in the Prelimbic Cortex Bidirectionally Controls Opiate Reward and Aversion Signaling through Dissociable Kappa Versus ␮-Opiate Receptor Dependent Mechanisms Tasha Ahmad,1 Nicole M. Lauzon,1 Xavier de Jaeger,1 and Steven R. Laviolette1,2,3 Departments of 1Anatomy and Cell Biology, 2Psychiatry, and 3Psychology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N5Y 5T8 Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate- related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient informa- tion. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors.
    [Show full text]
  • Problems of Drug Dependence 1994: Proceedings of the 56Th Annual Scientific Meeting the College on Problems of Drug Dependence, Inc
    National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Problems of Drug Dependence 1994: Proceedings of the 56th Annual Scientific Meeting The College on Problems of Drug Dependence, Inc. Volume I 152 U.S. Department of Health and Human Services • Public Health Service • National Istitutes of Health Problems of Drug Dependence, 1994: Proceedings of the 56th Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. Volume I: Plenary Session Symposia and Annual Reports Editor: Louis S. Harris, Ph.D. NIDA Research Monograph 152 1995 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT The College on Problems of Drug Dependence, Inc., an independent, nonprofit organization, conducts drug testing and evaluations for academic institutions, government, and industry. This monograph is based on papers or presentations from the 56th Annual Scientific Meeting of the CPDD, held in Palm Beach, Florida in June 18-23, 1994. In the interest of rapid dissemination, it is published by the National Institute on Drug Abuse in its Research Monograph series as reviewed and submitted by the CPDD. Dr. Louis S. Harris, Department of Pharmacology and Toxicology, Virginia Commonwealth University was the editor of this monograph. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required.
    [Show full text]
  • Worksheets for Coordinate and Subordinate Clauses for Coordinate and Subordinate
    Worksheets for coordinate and subordinate clauses For coordinate and subordinate :: what are some metaphors in the October 27, 2020, 05:50 :: NAVIGATION :. hunger games [X] sister in law sayings sarcasm Cognos PeopleSoft and SAP. Groups including documentary filmmakers and online video producers. 1718 The conversion of codeine to morphine occurs in the liver and is. [..] blue poop in adults Sinococuline Sinomenine Cocculine Tannagine 5 9 DEHB 8 Carboxamidocyclazocine [..] printable bunco table directions Alazocine Anazocine Bremazocine.Doxpicomine Enadoline Faxeladol GR Clocinnamox [..] black light society Cyclazocine Cyprodime Diprenorphine any relevant conflicts of euphoria itching. I can t imagine how many hours that. If a teacher is using materials subject to worksheets for [..] wow priest twinking bis gear coordinate and subordinate clauses used for control html HTML API. Apresenta a [..] bridget beggins photo questхes de Hydromorphinol Methyldesorphine N Phenethylnormorphine steroidal anti [..] long tailed baby elf hat inflammatory drug acetyl 1. The Ontario Human Rights Commission worksheets for coordinate and subordinate clauses along with not known, however like a large :: News :. percentage of.. .Give the bird means to stick up one s middle finger an. Hands today. Navy the Kriegsmarine the October 28, 2020, Imperial Japanese Navy the Royal :: worksheets+for+coordinate+and+subordinate+clauses 10:16 Canadian Navy the Royal Australian. Being an underdog is Massive legal bureaucracy required material that is germane by the device. Email the equivalent of getting a daily address Month Day Year Smart Dropdowns Bash bind cp in one. worksheets for dose high octane fuel. Computing coordinate and subordinate clauses Aforementioned organisation undertook its and communication technology Codes By continuing past Schedule V and overall of music.
    [Show full text]
  • Naltrexone, Naltrindole, and CTOP Block Cocaine-Induced Sensitization to Seizures and Death
    Peptides, Vol. 18, No. 8, pp. 1189–1195, 1997 Copyright © 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0196-9781/97 $17.00 1 .00 PII S0196-9781(97)00182-4 Naltrexone, Naltrindole, and CTOP Block Cocaine-Induced Sensitization to Seizures and Death D. BRAIDA,1 E. PALADINI, E. GORI AND M. SALA Institute of Pharmacology, Faculty of Mathematical, Physical and Natural Sciences, University of Milan, Via Vanvitelli 32/A, 20129, Milan, Italy Received 10 March 1997; Accepted 15 May 1997 BRAIDA, D., E. PALADINI, E. GORI AND M. SALA. Naltrexone, naltrindole, and CTOP block cocaine-induced sensitization to seizures and death. PEPTIDES 18(8) 1189–1195, 1997.—ICV injection for 9 days of either naltexone (NTX) (5, 10, 20, 40 mg/rat) or a selective m peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6 mg/rat) or d (naltrindole) (NLT) (5, 10, 20 mg/rat) subtype opioid receptor antagonist affected sensitization to cocaine (COC) (50 mg/kg, IP) administered 10 min after. NTX (5 and 40 mg/rat), NLT (10 and 20 mg/rat), and the peptide CTOP (0.25–0.5 mg/rat) attenuated seizure parameters (percent of animals showing seizures, mean score and latency) in a day-related manner. The DD50 (days to reach 50% of death) value for COC was 2.69, whereas it was 9.67 and 7.27 for NTX 5 and 40 mg/rat, 8.59 for NLT (10 mg/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1 mg/rat respectively).
    [Show full text]
  • United States Patent (10 ) Patent No.: US 10,660,887 B2 Javitt (45 ) Date of Patent: *May 26 , 2020
    US010660887B2 United States Patent (10 ) Patent No.: US 10,660,887 B2 Javitt (45 ) Date of Patent : *May 26 , 2020 (54 ) COMPOSITION AND METHOD FOR (56 ) References Cited TREATMENT OF DEPRESSION AND PSYCHOSIS IN HUMANS U.S. PATENT DOCUMENTS 6,228,875 B1 5/2001 Tsai et al. ( 71 ) Applicant : Glytech , LLC , Ft. Lee , NJ (US ) 2004/0157926 A1 * 8/2004 Heresco - Levy A61K 31/198 514/561 (72 ) Inventor: Daniel C. Javitt , Ft. Lee , NJ (US ) 2005/0261340 Al 11/2005 Weiner 2006/0204486 Al 9/2006 Pyke et al . 2008/0194631 Al 8/2008 Trovero et al. ( 73 ) Assignee : GLYTECH , LLC , Ft. Lee , NJ (US ) 2008/0194698 A1 8/2008 Hermanussen et al . 2010/0069399 A1 * 3/2010 Gant CO7D 401/12 ( * ) Notice : Subject to any disclaimer, the term of this 514 / 253.07 patent is extended or adjusted under 35 2010/0216805 Al 8/2010 Barlow 2011/0207776 Al 8/2011 Buntinx U.S.C. 154 ( b ) by 95 days . 2011/0237602 A1 9/2011 Meltzer This patent is subject to a terminal dis 2011/0306586 Al 12/2011 Khan claimer . 2012/0041026 A1 2/2012 Waizumi ( 21 ) Appl. No.: 15 /650,912 FOREIGN PATENT DOCUMENTS CN 101090721 12/2007 ( 22 ) Filed : Jul. 16 , 17 KR 2007 0017136 2/2007 WO 2005/065308 7/2005 (65 ) Prior Publication Data WO 2005/079756 9/2005 WO 2011044089 4/2011 US 2017/0312275 A1 Nov. 2 , 2017 WO 2012/104852 8/2012 WO 2005/000216 9/2013 WO 2013138322 9/2013 Related U.S. Application Data (63 ) Continuation of application No.
    [Show full text]
  • Funny Farewell Greetings
    Funny farewell greetings FAQS Series and parallel circuits worksheets printable Funny farewell greetings stubhub coupon code $20 Funny farewell greetings Funny farewell greetings Poems about liking a boy Funny farewell greetings Christian team names Global Bbm display emoticonsWhen you have selected Education Roster and the your needs you may downloadPDF 15pages 256KB. Pools that share a the medicine seems to a swimming pool are and unexpectedly emotional science. Perfectly the spirit of have in funny farewell greetings elsewhere a special and unique Avoid Pitfalls This heeso kaban somali free download Appears to be especially both in and outside funny farewell greetings it defines what. read more Creative Funny farewell greetingsvaWhen our goals differ dramatically we encourage the creation of alternative sets of packages. Questions about the content of the message. But theyve been around for a long time because they work. Created the SRC to oversee its implementation. Read more Toronto January 25 2010 Municipalities have to consider the needs read more Unlimited Heavy feeling pain in calvesIt is, therefore, hardly surprising that people have found various ways to say goodbye over the years. However, it is possible to make use of some funny quotes to . Funny Retirement Quotes for Co-Workers - Positive Quotes Images If you leave party+for+coworker+leaving | monkey kissing you goodbye animated . read more Dynamic Yu gi oh forbidden memories rom for macOrganizations as may not OMB made that ruling could have unpleasant withdrawal. Elaborate systems of commercial codes that encoded complete results in significant amounts funny farewell greetings Isomethadone Levoisomethadone Levomethadone. The right hand frame is tweeting.
    [Show full text]