DOCSLIB.ORG

Tuesday, December 14 Poster Session II

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Neuropsychopharmacology (2004) 29, S127-S182 © 2004 Nature Publishing Group All rights reserved 0893-133X/04 www.neuropsychopharmacology.org S127 Tuesday, December 14 that does not activate ganglion or muscle-type nicotinic acetylcholine Poster Session II - Tuesday receptors. It is orally active, has shown long lasting cognitive effects in animal models and neuroprotective effects in vitro. Methods: Four early placebo-controlled studies in humans have been completed and 1. Effect of Memantine on Behavioral Outcomes in Moderate to partial data from a fifth are available (N=124). The completed stud- Severe Alzheimer’s Disease ies include SRD, MRD, food interaction and a PK in the elderly. Sin- Jeffrey L Cummings*,Eugene Schneider, Pierre N Tariot and gle doses up to 320mg and multiple doses for 10 days up to 200mg, Stephen M Graham have been explored. An ongoing study in elderly subjects with age as- Department of Neurology, University of California Los Angeles, Los sociated memory impairment (AAMI) involves three-week dosing up Angeles, CA, USA to 150mg. Safety/Tolerability: The drug was well tolerated overall. No changes of clinical significance were detected on biochemistry Memantine is a low-moderate affinity, uncompetitive N- testing, urine analysis, vital signs, ECG or 24-hour Holter monitor- methyl-D-aspartate (NMDA) receptor antagonist approved for the ing. Adverse events (AEs) were mild to moderate in intensity. Severe treatment of moderate to severe Alzheimer’s disease (AD). Excitotox- AEs were only seen at MTD - identifed in these studies as 320mg in icity mediated by NMDA receptors is thought to play a role in the the young and 150mg in the elderly. Dose limiting AEs included pathogenesis of AD. Memantine blocks prolonged pathological acti- headache, dizziness, lightheadedness, and occasional nausea/vomit- vation of NMDA receptors while allowing normal receptor function. ing. Since no changes in CV variables accompanied these AEs, we This analysis of a 24-week double-blind, placebo-controlled trial con- have concluded they were due to the central pharmacology of TC- ducted in moderate to severe AD patients (N=404) assessed the effect 1734. Central Activity: Clear evidence of CNS penetration was found of memantine on behavioral symptoms in moderate to severe AD pa- after single dosing and multiple dosing (10 days). Pharmaco-EEG tients receiving stable donepezil treatment. The trial demonstrated showed acceleration type changes with power shift from the high significant benefits of memantine on functional, cognitive, and global theta, low alpha range to high alpha, low beta range. There was good measures. Behavioral symptoms were assessed using the Neuropsy- correlation between plasma levels of TC-1734 and pharmaco-EEG chiatric Inventory (NPI), administered at baseline, Week 12 and Week changes. Cognitive enhancement: Cognitive effects were evaluated 24. The statistical analysis (ANCOVA) was based on the ITT popula- using factors measured by the CDR cognitive test battery. In the tion using an LOCF approach. Baseline characteristics between the MRD study, a difference was seen between drug and placebo at day 10 placebo and memantine groups were comparable. At Week 24, there on the Power of Attention factor. In the elderly PK study, improve- was a statistically significant treatment difference (P=.002), with a re- ment was seen on the Quality of Episodic Memory factor. This effect duction in behavioral disturbances and psychiatric symptoms in me- was most pronounced in the period 36-48 hours (the last time points mantine-treated patients and worsening in placebo-treated patients. assessed) following a single 80mg dose. The long duration of action In addition, several NPI domains demonstrated statistically signifi- is similar to that seen in animal models and suggests dosing once cant treatment differences in favor of memantine at Week 24. These daily may be appropriate. In elderly AAMI subjects who received domains were agitation/aggression (P=.001), irritability/lability 50mg doses, there were robust differences between drug and placebo (P=.005) and appetite/eating change (P=.045). When patients on the Power of Attention and Continuity of Attention factors. A dif- asymptomatic at baseline were examined, significantly fewer meman- ference was also seen on the Speed of Memory factor. There were tine patients exhibited emergence of delusions (P=.011) and agita- some differences seen on the Quality of Episodic Memory factor, but tion/aggression (P=.032) at Week 12 and agitation/aggression none on the Quality of Working Memory factor. These 50mg results (P=.016), irritability/lability (P=.041) and nighttime behavioral dis- were statistically significant. Improvements in the 100mg cohort turbances (P=.027) at Week 24 compared to placebo patients. When were less prominent, suggesting a possible inverted U-dose response patients symptomatic at baseline were examined, there was signifi- curve. Again this is consistent with animal findings and with results cantly less worsening compared to placebo in symptoms of agita- seen with many drugs that enhance cognition. Conclusions: TC- tion/aggression (P=.018, Week 12; P=.021, Week 24) and 1734 was well tolerated in early studies in humans. Unlike other appetite/eating changes (P=.012, Week 12). Effective treatment of NNR agonists, it did not cause peripheral CV effects or, except at the these behaviors is important for this patient population with respect MTD, nausea/vomiting. At a dose of 50mg, TC-1734 enhanced atten- to both quality of life and the potential for reducing caregiver burden. tion, memory and speed of cognition in a group of elderly subjects Aging; Neurodegenerative disorders with AAMI. Cognition; Nicotine 2. TC-1734: A Neuronal Nicotinic Acetylcholine Receptor Partial Agonist that Demonstrated an Excellent Safety/Tolerabililty 3. Using The Tryptophan Depletion Paradigm to Examine The Profile and Cognitive Enhancement in Early Studies in Humans Relationship Between Estrogen and Serotonin In Modulating Geoffrey C Dunbar* Mood and Cognition in Menopausal Women Cynthia N Epperson*,Ralitza Gueorguieva, John H Krystal, Clinical Development and Regulatory Affairs, Targacept Inc, Winston George Heninger and Zenab Amin Salem, NC, USA Sponsor: Raymond Bartus Psychiatry, Yale University, New Haven, CT, USA; Obstetrics/Gynecology, Yale University, New Haven, CT, USA Background: Neuronal nicotinic acetylcholine receptor(NNR) agonists are believed capable of affecting various aspects of cognition, Sponsor: Stephanie O’Malley including attention, memory and learning, in both normal and cog- nitively impaired subjects. Previous NNR agonists have lacked suffi- Background: Changes in neuroendocrine function may predis- cient selectivity for the CNS and their development terminated due to pose menopausal women to psychological disturbances characterized peripheral side effects like nausea/vomiting and cardiovascular (CV) by depressed mood, anxiety, irritability, fatigue, insomnia, forgetful- changes. TC-1734 is a selective partial agonsit at the CNS α4β2 NNR ness and decline in libido. The acute tryptophan (TRP) depletion ACNP 2004 Annual Meeting S128 paradigm was employed to examine serotonergic contribution to problem. Methods:5focus groups (N=30) consisting of four to mood and cognitive function in menopausal women who were seven participants each were conducted at the Medical University of within four weeks of recovery from an episode of major depression South Carolina and community locations. A brief demographic and in healthy menopausal women pre and post treatment with es- survey was completed at the beginning of the focus groups. A trogen. Methods: Menopausal women with depression that was re- seven-item focus group discussion guide was developed and focus sponsive to treatment with estradiol 75 ug/d (N=4); the selective groups were conducted by a trained moderator. All sessions were serotonin reuptake inhibitor (SSRI) fluoxetine 20-40 mg/d (n=4); or tape-recorded and transcribed. Nonnumerical Unstructured Data estradiol 75 ug/d and fluoxetine 20 mg/d (N=3) and peri and post Indexing Search and Theory Building was utilized to code and ana- menopausal healthy controls (N=18) underwent active and sham lyze the transcripts. Results:All participants self-identified them- TRP depletion sessions. Healthy menopausal women underwent the selves as African American. Participants were 55 years of age and procedures both before and after estradiol 75 ug/d treatment (ET) for older. Analysis of transcripts revealed recurring focus groups 3 months. Mood and cognition were assessed using standard clinician themes that may influence the decision making process. Partici- administered tests before and 6 hours after administration of the pants expressed similar beliefs and thoughts about Alzheimer’s dis- amino acid mixture. Results: Although active TRP depletion re- ease symptoms. They expressed self-concerns about their own sulted in an 89% decline in total and free plasma TRP levels, neither memory often elaborating on their confusion about normal aging menopausal women who had recently recovered from an episode of versus dementia. They stressed concerns about the length of time major depressive disorder (MDD) or healthy menopausal women pre from awareness of symptoms to the physician’s diagnosis. They ap- or post estrogen administration experienced a worsening of their peared to lack the knowledge that there are medications indicated in mood during active tryptophan depletion. In contrast,
Recommended publications
  • Dextromethorphan Attenuates Sensorineural Hearing Loss in an Animal Model and Population-Based Cohort Study

    Dextromethorphan Attenuates Sensorineural Hearing Loss in an Animal Model and Population-Based Cohort Study

    International Journal of Environmental Research and Public Health Article Dextromethorphan Attenuates Sensorineural Hearing Loss in an Animal Model and Population-Based Cohort Study Hsin-Chien Chen 1,* , Chih-Hung Wang 1,2 , Wu-Chien Chien 3,4 , Chi-Hsiang Chung 3,4, Cheng-Ping Shih 1, Yi-Chun Lin 1,2, I-Hsun Li 5,6, Yuan-Yung Lin 1,2 and Chao-Yin Kuo 1 1 Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; [email protected] (C.-H.W.); [email protected] (C.-P.S.); [email protected] (Y.-C.L.); [email protected] (Y.-Y.L.); [email protected] (C.-Y.K.) 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan 3 School of Public Health, National Defense Medical Center, Taipei 114, Taiwan; [email protected] (W.-C.C.); [email protected] (C.-H.C.) 4 Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan 5 Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; [email protected] 6 School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan * Correspondence: [email protected]; Tel.: +886-2-8792-7192; Fax: +886-2-8792-7193 Received: 31 July 2020; Accepted: 28 August 2020; Published: 31 August 2020 Abstract: The effect of dextromethorphan (DXM) use in sensorineural hearing loss (SNHL) has not been fully examined. We conducted an animal model and nationwide retrospective matched-cohort study to explore the association between DXM use and SNHL.
  • Association Analyses of Known Genetic Variants with Gene

    Association Analyses of Known Genetic Variants with Gene

    ASSOCIATION ANALYSES OF KNOWN GENETIC VARIANTS WITH GENE EXPRESSION IN BRAIN by Viktoriya Strumba A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Bioinformatics) in The University of Michigan 2009 Doctoral Committee: Professor Margit Burmeister, Chair Professor Huda Akil Professor Brian D. Athey Assistant Professor Zhaohui S. Qin Research Statistician Thomas Blackwell To Sam and Valentina Dmitriy and Elizabeth ii ACKNOWLEDGEMENTS I would like to thank my advisor Professor Margit Burmeister, who tirelessly guided me though seemingly impassable corridors of graduate work. Throughout my thesis writing period she provided sound advice, encouragement and inspiration. Leading by example, her enthusiasm and dedication have been instrumental in my path to becoming a better scientist. I also would like to thank my co-advisor Tom Blackwell. His careful prodding always kept me on my toes and looking for answers, which taught me the depth of careful statistical analysis. His diligence and dedication have been irreplaceable in most difficult of projects. I also would like to thank my other committee members: Huda Akil, Brian Athey and Steve Qin as well as David States. You did not make it easy for me, but I thank you for believing and not giving up. Huda’s eloquence in every subject matter she explained have been particularly inspiring, while both Huda’s and Brian’s valuable advice made the completion of this dissertation possible. I would also like to thank all the members of the Burmeister lab, both past and present: Sandra Villafuerte, Kristine Ito, Cindy Schoen, Karen Majczenko, Ellen Schmidt, Randi Burns, Gang Su, Nan Xiang and Ana Progovac.
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active

    TABLE 1 Studies of Antagonist Activity in Constitutively Active

    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
  • Efficacy and Mechanistic Evaluation of Tic10, a Novel Antitumor Agent

    Efficacy and Mechanistic Evaluation of Tic10, a Novel Antitumor Agent

    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Joshua Edward Allen University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Oncology Commons Recommended Citation Allen, Joshua Edward, "Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent" (2012). Publicly Accessible Penn Dissertations. 488. https://repository.upenn.edu/edissertations/488 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/488 For more information, please contact [email protected]. Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Abstract TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells and is a critical effector in the immune surveillance of cancer. Recombinant TRAIL and TRAIL-agonist antibodies are in clinical trials for the treatment of solid malignancies due to the cancer-specific cytotoxicity of TRAIL. Recombinant TRAIL has a short serum half-life and both recombinant TRAIL and TRAIL receptor agonist antibodies have a limited capacity to perfuse to tissue compartments such as the brain, limiting their efficacy in certain malignancies. To overcome such limitations, we searched for small molecules capable of inducing the TRAIL gene using a high throughput luciferase reporter gene assay. We selected TRAIL-inducing compound 10 (TIC10) for further study based on its induction of TRAIL at the cell surface and its promising therapeutic index. TIC10 is a potent, stable, and orally active antitumor agent that crosses the blood-brain barrier and transcriptionally induces TRAIL and TRAIL-mediated cell death in a p53-independent manner.
  • Galantamine Potentiates the Neuroprotective Effect of Memantine Against NMDA-Induced Excitotoxicity Joao~ P

    Galantamine Potentiates the Neuroprotective Effect of Memantine Against NMDA-Induced Excitotoxicity Joao~ P

    Galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity Joao~ P. Lopes1, Glauco Tarozzo1, Angelo Reggiani1, Daniele Piomelli1,2 & Andrea Cavalli1,3 1D3 – Drug Discovery and Development Department, Istituto Italiano di Tecnologia, Via Morego, 16163, Genova, Italy 2Departments of Anatomy and Neurobiology and Biological Chemistry, University of California, Irvine, CA, 92697-4621 3Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, Bologna University, Via Belmeloro, 40126, Bologna, Italy Keywords Abstract Alzheimer’s disease, drug combination, N NMDA neurotoxicity, NR2B, The combination of memantine, an -methyl-D-aspartate (NMDA) receptor polypharmacology, primary cortical neurons antagonist, with an acetylcholinesterase inhibitor (AChEI) is the current stan- dard of care in Alzheimer’s disease (AD). Galantamine, an AChEI currently Correspondence marketed for the treatment of AD, exerts memory-enhancing and neuroprotec- Andrea Cavalli, D3 – Drug Discovery and tive effects via activation of nicotinic acetylcholine receptors (nAChRs). Here, Development Department, Istituto Italiano we investigated the neuroprotective properties of galantamine in primary cul- di Tecnologia – Via Morego, 30, 16163 tures of rat cortical neurons when given alone or in combination with meman- Genova, Italy. Tel: +39 010 71781530; Fax: +39 010 tine. In agreement with previous findings, we found that memantine was fully 71781228; E-mail: [email protected] effective in reversing NMDA toxicity at concentrations of 2.5 and 5 lmol/L. Galantamine also completely reversed NMDA toxicity at a concentration of Funding Information 5 lmol/L. The a7 and a4b2 nAChR antagonists, methyllycaconitine, and dihy- No funding information provided. dro-b-erythroidine blocked the neuroprotective effect of galantamine, demon- strating the involvement of nAChRs.
  • The Medical Management of Depression

    The Medical Management of Depression

    The new england journal of medicine review article drug therapy The Medical Management of Depression J. John Mann, M.D. ecurrent episodes of major depression, which is a common From the Department of Neuroscience, and serious illness, are called major depressive disorder; depressive episodes New York State Psychiatric Institute– r Columbia University College of Physicians that occur in conjunction with manic episodes are called bipolar disorder. and Surgeons, New York. Address reprint Major depressive disorder accounts for 4.4 percent of the total overall global disease requests to Dr. Mann at the Department of burden, a contribution similar to that of ischemic heart disease or diarrheal diseases.1 Neuroscience, New York State Psychiatric 2 Institute, 1051 Riverside Dr., Box 42, New The prevalence of major depressive disorder in the United States is 5.4 to 8.9 percent York, NY 10032, or at [email protected]. and of bipolar disorder, 1.7 to 3.7 percent.3 Major depression affects 5 to 13 percent of medical outpatients,4 yet is often undiagnosed and untreated.5,6 Moreover, it is often N Engl J Med 2005;353:1819-34. undertreated when correctly diagnosed.6 Copyright © 2005 Massachusetts Medical Society. The demographics of depression are impressive. Among persons both with major depressive disorder and bipolar disorder, 75 to 85 percent have recurrent episodes.7,8 In addition, 10 to 30 percent of persons with a major depressive episode recover incom- pletely and have persistent, residual depressive symptoms, or dysthymia, a disorder with symptoms
  • Treatment Protocol Copyright © 2018 Kostoff Et Al

    Treatment Protocol Copyright © 2018 Kostoff Et Al

    Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention.
  • Evidence That Mcpp May Have Behavioural Effects Mediated by Central 5-Ht1c Receptors 1G.A

    Evidence That Mcpp May Have Behavioural Effects Mediated by Central 5-Ht1c Receptors 1G.A

    Br. J. Pharmacol. (1988), 94, 137-147 Evidence that mCPP may have behavioural effects mediated by central 5-HT1c receptors 1G.A. Kennett & G. Curzon Department of Neurochemistry, Institute of Neurology, Queen Square, London WC1N 3BG 1 The effects of 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP) on activity of rats in a novel cage, and on the rotorod and elevated bar co-ordination tests was examined. 2 Peripherally administered mCPP and TFMPP dose-dependently reduced locomotion, rearing, and feeding scores but not grooming of freely fed rats placed in a novel observation cage. Yawning behaviour was increased. Similar effects were also observed after injection of mCPP into the 3rd ventricle. 3 Co-ordination on a rotating drum of both untrained and trained rats was impaired following mCPP but co-ordination on an elevated bar was not. 4 The hypoactivity induced by mCPP was opposed by three antagonists with high affinity for the 5-hydroxytryptamine (5-HT1c) site; metergoline, mianserin, cyproheptadine and possibly also by a fourth antagonist mesulergine. Metergoline, mianserin and cyproheptadine also opposed the reduction in feeding scores. However, neither effect of mCPP was antagonized by the 5-HT2-receptor antagonists ketanserin or ritanserin, the 5-HT3-receptor antagonist ICS 205-930, the 5-HTlA and 5-HTIB-receptor antagonists (-)-pindolol, (-)-propranolol and (±)-cyanopindolol or the 5-HTIA-, 5-HT2- and dopamine receptor antagonist spiperone. The specific a2-adrenoceptor antagonist idazoxan was also without effect. 5 Hypoactivity induced by TFMPP was similarly antagonized by mianserin but unaffected by (±+-cyanopindolol. 6 These results suggest that the hypoactivity is mediated by central 5-HT1c-receptors and that mCPP and possibly TFMPP may be 5-HT1c-receptor agonists.
  • Mixed Antagonistic Effects of the Ginkgolides at Recombinant Human R1 GABAC Receptors

    Mixed Antagonistic Effects of the Ginkgolides at Recombinant Human R1 GABAC Receptors

    Neuropharmacology 63 (2012) 1127e1139 Contents lists available at SciVerse ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Mixed antagonistic effects of the ginkgolides at recombinant human r1 GABAC receptors Shelley H. Huang a, Trevor M. Lewis b, Sarah C.R. Lummis c, Andrew J. Thompson c, Mary Chebib d, Graham A.R. Johnston a, Rujee K. Duke a,* a Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of Sydney, Australia b School of Medical Sciences, University of New South Wales, Australia c Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom d Faculty of Pharmacy, University of Sydney, Australia article info abstract Article history: The diterpene lactones of Ginkgo biloba, ginkgolides A, B and C are antagonists at a range of Cys-loop Received 11 July 2011 receptors. This study examined the effects of the ginkgolides at recombinant human r1 GABAC recep- Received in revised form tors expressed in Xenopus oocytes using two-electrode voltage clamp. The ginkgolides were moderately 18 June 2012 potent antagonists with IC sinthemM range. At 10 mM, 30 mM and 100 mM, the ginkgolides caused Accepted 24 June 2012 50 rightward shifts of GABA doseeresponse curves and reduced maximal GABA responses, characteristic of noncompetitive antagonists, while the potencies showed a clear dependence on GABA concentration, Keywords: indicating apparent competitive antagonism. This suggests that the ginkgolides exert a mixed-type Ginkgolide Bilobalide antagonism at the r1 GABAC receptors. The ginkgolides did not exhibit any obvious use-dependent Mixed-antagonism inhibition. Fitting of the data to a number of kinetic schemes suggests an allosteric inhibition as Use-dependent a possible mechanism of action of the ginkgolides which accounts for their inhibition of the responses GABAr receptor without channel block or use-dependent inhibition.
  • Polymorphic Regions of the Estrogen Receptor, Androgen Receptor and Serotonin Transporter Genes and Their Association with Mood Variability in Young Women

    Polymorphic Regions of the Estrogen Receptor, Androgen Receptor and Serotonin Transporter Genes and Their Association with Mood Variability in Young Women

    Lakehead University Knowledge Commons,http://knowledgecommons.lakeheadu.ca Electronic Theses and Dissertations Retrospective theses 2006 Polymorphic regions of the estrogen receptor, androgen receptor and serotonin transporter genes and their association with mood variability in young women Richards, Meghan A. http://knowledgecommons.lakeheadu.ca/handle/2453/3361 Downloaded from Lakehead University, KnowledgeCommons Polymorphic Regions 1 Ruimmg head: GENETIC POLYMORPHISMS AND MOOD Polymorphic Regions of the Estrogen Receptor, Androgen Receptor and Serotonin Transporter Genes and their Association with Mood Variability in Young Women Meghan A. Richards M.A. Thesis Lakehead University Supervisor: Dr. Kirsten Oinonen copyright © Meghan Richards, 2006 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Library and Bibliothèque et 1^1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-21539-5 Our file Notre référence ISBN: 978-0-494-21539-5 NOTICE: AVIS: The author has granted a non­ L'auteur a accordé une licence non exclusive exclusive license allowing Library permettant à la Bibliothèque et Archives and Archives Canada to reproduce,Canada de reproduire, publier, archiver, publish, archive, preserve, conserve,sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet,distribuer et vendre des thèses partout dans loan, distribute and sell theses le monde, à des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, électronique commercial purposes, in microform,et/ou autres formats.
  • The Effects of Dextromethorphan on Response Acquisition with Delayed Reinforcement

    The Effects of Dextromethorphan on Response Acquisition with Delayed Reinforcement

    Western Michigan University ScholarWorks at WMU Dissertations Graduate College 6-2005 The Effects of Dextromethorphan on Response Acquisition with Delayed Reinforcement Thomas B. Morgan Western Michigan University Follow this and additional works at: https://scholarworks.wmich.edu/dissertations Part of the Mental and Social Health Commons, and the Psychology Commons Recommended Citation Morgan, Thomas B., "The Effects of Dextromethorphan on Response Acquisition with Delayed Reinforcement" (2005). Dissertations. 1050. https://scholarworks.wmich.edu/dissertations/1050 This Dissertation-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Dissertations by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. THE EFFECTS OF DEXTROMETHORPHAN ON RESPONSE ACQUISITION WITH DELAYED REINFORCEMENT by Thomas B. Morgan A Dissertation Submitted to the Faculty of The Graduate College in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Department of Psychology Western Michigan University Kalamazoo, Michigan June 2005 THE EFFECTS OF DEXTROMETHORPHAN ON RESPONSE ACQUISITION WITH DELAYED REINFORCEMENT Thomas B. Morgan, Ph. D. Western Michigan University, 2005 The current study examined in 2-h sessions the effects of intraperitoneal injec- tions of dextromethorphan (DM) (0.0, 40.0, 60.0, and 80.0 mg/kg) on the acquisition of lever-press responding in rats that were exposed to a two-lever procedure in which responses on the reinforcement lever (RL) were reinforced with food after a 15-s re- setting delay and responses on the cancellation lever cancelled a scheduled reinforcer.
  • Ligand-Gated Ion Channels' British Journal of Pharmacology, Vol

    Ligand-Gated Ion Channels' British Journal of Pharmacology, Vol

    Edinburgh Research Explorer The Concise Guide to PHARMACOLOGY 2015/16 Citation for published version: Alexander, SP, Peters, JA, Kelly, E, Marrion, N, Benson, HE, Faccenda, E, Pawson, AJ, Sharman, JL, Southan, C, Davies, JA & CGTP Collaborators 2015, 'The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels' British Journal of Pharmacology, vol. 172, no. 24, pp. 5870-5903. DOI: 10.1111/bph.13350 Digital Object Identifier (DOI): 10.1111/bph.13350 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: British Journal of Pharmacology General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 05. Apr. 2019 S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels. British Journal of Pharmacology (2015) 172, 5870–5903 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Ligand-gated ion channels Stephen PH Alexander1,