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Role of Prefrontal Cortex and Cholinergic Modulation in Attentional
Role of prefrontal cortex and cholinergic modulation in attentional performance in rats Beth Mary Fisher Department of Psychology Downing College University of Cambridge September 2017 This dissertation is submitted for the degree of Doctor of Philosophy Declaration This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. It does not exceed the prescribed word limit of the degree committee for the faculty of biology of 60,000 words. i2 Acknowledgements Firstly, I would like to thank my supervisor Tim Bussey and advisor Trevor Robbins for their invaluable support, guidance and encouragement throughout my PhD. Their insightful scientific discussions, passion for the field and praise of me, have shaped me to become a scientist I am proud of, and given me an unknown confidence. Not only are they experts in the field, but they are down to earth, kind and fun. -
Hayward Et Al, 2017
European Neuropsychopharmacology (]]]]) ], ]]]–]]] www.elsevier.com/locate/euroneuro Partial agonism at the α7 nicotinic acetylcholine receptor improves attention, impulsive action and vigilance in low attentive rats Andrew Haywardn, Lisa Adamson, Joanna C. Neilln Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester M13 9PT, UK Received 7 July 2016; received in revised form 9 January 2017; accepted 18 January 2017 KEYWORDS Abstract 5 choice-continuous Inattention is a disabling symptom in conditions such as schizophrenia and attention deficit/ performance task; hyperactivity disorder. Nicotine can improve attention and vigilance, but is unsuitable for clinical use 5C-CPT; due to abuse liability. Genetic knockout of the α7 nicotinic acetylcholine receptor (nAChR) induces α 7 nAChR; attention deficits therefore selective agonism may improve attention, without the abuse liability Animal Model; associated with nicotine. The α7 nAChR partial agonist encenicline (formerly EVP-6124) enhances Behavioural separa- memory in rodents and humans. Here we investigate, for the first time, efficacy of encenicline to tion; Low attentive improve attention and vigilance in animals behaviourally grouped for low attentive traits in the 5 choice-continuous performance task (5C-CPT). Female Lister Hooded rats were trained to perform the5C-CPTwithavariablestimulusduration(SD).Animalswerethengroupedbasedonperformance intoupperandlowerquartilesofd0 (vigilance) and accuracy (selective attention), producing high- attentive (HA) and low-attentive (LA) groups. LA animals showed an increase in selective attention and vigilance at 0.3 mg/kg encenicline, a reduction in impulsive action (probability of false alarms) and increase in vigilance following 1 mg/kg at 0.75 s SD. At 1 mg/kg, HA animals had reduced selective attention at 0.75 s SD and reduced vigilance at 0.75 and 1.25 s SD. -
(Tert- Butoxycarbonyl)Amino](3 361442- 3
Alternative Name CAS 1. Product Name Use Number 320345- 2. Aclidinium bromide API 99-1 (2S)-[(tert- Butoxycarbonyl)amino](3 361442- 3. Saxagliptin int -hydroxyadamant-1- 00-4 yl)ethanoic acid 1,3- 1,3- 5001-18- 4. Dihydroxyadamantane Adamantanediol 3 1,3-Dimethyladamantane 702-79-4 memantine intermediate 5. 1-Acetylamido-3,5- 19982- 6. Memantine int dimethyladamantane 07-1 1- 7. 880-52-4 Acetylaminoadamantane 1- 4942-47- 8. 1-Adamantaneacetic acid Adamantylacetic 6 acid [2-(1- 6240-11- 9. 1-Adamantaneethanol Adamantylethano 5 l)] 1- 10. 1-Adamantanemethanol Adamantylmetha 770-71-8 nol 1- 1660-04- 1-Adamantyl methyl rimantadine intermediate; 11. Acetyladamantan 4 ketone e 1-Chloro-3,5- 707-36-8 memantine intermediate; 12. dimethyladamantane 1-Hydroxy-3,5- memantine intermediate; 13. 707-37-9 dimethyladamantane 2- 14. 2-Adamantanol Hydroxyadamant 700-57-2 ane 15. 2-Adamantanone 700-58-3 2-Aminoadamantane 10523- 16. hydrochloride 68-9 3-Amino-1-hydroxy- 3-Amino-1- 702-82-9 vildagliptin intermediate; 17. adamantane adamantanol 3- 38584- 18. (Hydroxymethyl)adamant 37-1 -1-ol 19. 3-aminomethyl- 865887- mequitazine intermediate; 20. quinuclidine 14-5 dihydrochloride zacopride intermediate; 6530-09- mezacopride intermediate; 3-Aminoquinuclidine 21. 2 pancopride intermediate; dihydrochloride azasetron intermediate; 3-Carbethoxy-dehydro- quifenadine intermediate; 50790- 22. quinuclidine sequifenadine intermediate; 85-7 hydrochloride quifenadine intermediate; 3- 6238-33- 23. sequifenadine intermediate; Carbethoxyquinuclidine 1 3-hydroxymethyl 79221- mequitazine intermediate; 24. quinuclidine 75-3 hydrochloride 3-Quinuclidine 6238-34- 25. carboxylic acid 2 hydrochloride 1619-34- penehyclidine intermediate; 26. 3-Quinuclidinol 7 clidinium intermediate; cevimeline intermediate; 3-Quinuclidinone 1193-65- 27. -
Gene Expression Studies in Depression Development and Treatment
Mariani et al. Translational Psychiatry (2021) 11:354 https://doi.org/10.1038/s41398-021-01469-6 Translational Psychiatry REVIEW ARTICLE Open Access Gene expression studies in Depression development and treatment: an overview of the underlying molecular mechanisms and biological processes to identify biomarkers Nicole Mariani 1, Nadia Cattane2,CarminePariante 1 and Annamaria Cattaneo 2,3 Abstract A combination of different risk factors, such as genetic, environmental and psychological factors, together with immune system, stress response, brain neuroplasticity and the regulation of neurotransmitters, is thought to lead to the development of major depressive disorder (MDD). A growing number of studies have tried to investigate the underlying mechanisms of MDD by analysing the expression levels of genes involved in such biological processes. These studies have shown that MDD is not just a brain disorder, but also a body disorder, and this is mainly due to the interplay between the periphery and the Central Nervous System (CNS). To this purpose, most of the studies conducted so far have mainly dedicated to the analysis of the gene expression levels using postmortem brain tissue as well as peripheral blood samples of MDD patients. In this paper, we reviewed the current literature on candidate gene expression alterations and the few existing transcriptomics studies in MDD focusing on inflammation, neuroplasticity, neurotransmitters and stress-related genes. Moreover, we focused our attention on studies, which have investigated 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; mRNA levels as biomarkers to predict therapy outcomes. This is important as many patients do not respond to antidepressant medication or could experience adverse side effects, leading to the interruption of treatment. -
Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. -
W O 2016/201373 A1 15 December 2016 (15.12.2016) W I PO I P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2016/201373 A1 15 December 2016 (15.12.2016) W I PO I P C T (51) International Patent Classification: (74) Agents: QUEIROZ DE OLIVEIRA, Pierre et al.; Pepper A61K31/17(2006.01) A61P 25/00 (2006.01) Hamilton LLP, 500 Grant Street, Suite 5000, Pittsburgh, A61K 31/415 (2006.01) PA 15219-2507 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated,for every PCT/US2016/037090 kind of national protection available): AE, AG, AL, AM, .) . AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filng Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 10 June 2016 (10.06.2016) DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/174,983 12 June 2015 (12.06.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/194,084 17 July 2015 (17.07.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. -
The Α7 Nicotinic Agonist ABT-126 in the Treatment
Neuropsychopharmacology (2016) 41, 2893–2902 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org The ɑ7 Nicotinic Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia in Nonsmokers: Results from a Randomized Controlled Phase 2b Study ,1 1 1,2 1 George Haig* , Deli Wang , Ahmed A Othman and Jun Zhao 1 2 Abbvie Inc., North Chicago, IL, USA; Faculty of Pharmacy, Cairo University, Cairo, Egypt A double-blind, placebo-controlled, parallel-group, 24-week, multicenter trial was conducted to evaluate the efficacy and safety of 3 doses of ABT-126, an α7 nicotinic receptor agonist, for the treatment of cognitive impairment in nonsmoking subjects with schizophrenia. Clinically stable subjects were randomized in 2 stages: placebo, ABT-126 25 mg, 50 mg or 75 mg once daily (stage 1) and placebo or ABT-126 50 mg (stage 2). The primary analysis was the change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score for ABT-126 50 mg vs placebo using a mixed-model for repeated-measures. A key secondary measure was the University of California Performance-based Assessment-Extended Range (UPSA-2ER). A total of 432 subjects were randomized and 80% (344/431) completed the study. No statistically significant differences were observed in either the change from baseline for the MCCB neurocognitive composite score (+2.66 [ ± 0.54] for ABT-126 50 mg vs +2.46 [ ± 0.56] for placebo at week 12; P40.05) or the UPSA-2ER. A trend for improvement was seen at week 24 on the 16-item Negative Symptom Assessment Scale total − ± − ± = score for ABT-126 50 mg (change from baseline 4.27 [0.58] vs 3.00 [0.60] for placebo; P 0.059). -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
Nicotinic Acetylcholine Receptors
nAChR Nicotinic acetylcholine receptors nAChRs (nicotinic acetylcholine receptors) are neuron receptor proteins that signal for muscular contraction upon a chemical stimulus. They are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the presynaptic and postsynaptic sides of theneuromuscular junction. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Like the other type of acetylcholine receptor-the muscarinic acetylcholine receptor (mAChR)-the nAChR is triggered by the binding of the neurotransmitter acetylcholine (ACh). Just as muscarinic receptors are named such because they are also activated by muscarine, nicotinic receptors can be opened not only by acetylcholine but also by nicotine —hence the name "nicotinic". www.MedChemExpress.com 1 nAChR Inhibitors & Modulators (+)-Sparteine (-)-(S)-B-973B Cat. No.: HY-W008350 Cat. No.: HY-114269 Bioactivity: (+)-Sparteine is a natural alkaloid acting as a ganglionic Bioactivity: (-)-(S)-B-973B is a potent allosteric agonist and positive blocking agent. (+)-Sparteine competitively blocks nicotinic allosteric modulator of α7 nAChR, with antinociceptive ACh receptor in the neurons. activity [1]. Purity: 98.0% Purity: 99.93% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in Water, Size: 10mM x 1mL in DMSO, 100 mg 5 mg, 10 mg, 50 mg, 100 mg (±)-Epibatidine A-867744 (CMI 545) Cat. No.: HY-101078 Cat. No.: HY-12149 Bioactivity: (±)-Epibatidine is a nicotinic agonist. (±)-Epibatidine is a Bioactivity: A-867744 is a positive allosteric modulator of α7 nAChRs (IC50 neuronal nAChR agonist. values are 0.98 and 1.12 μM for human and rat α7 receptor ACh-evoked currents respectively, in X. -
Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology
brain sciences Review Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology Andrea Becchetti 1,* , Laura Clara Grandi 1 , Giulia Colombo 1 , Simone Meneghini 1 and Alida Amadeo 2 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy; [email protected] (L.C.G.); [email protected] (G.C.); [email protected] (S.M.) 2 Department of Biosciences, University of Milano, 20133 Milano, Italy; [email protected] * Correspondence: [email protected] Received: 13 October 2020; Accepted: 21 November 2020; Published: 25 November 2020 Abstract: Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and β2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain. -
Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation
Neuropsychopharmacology (2018) 43, 583–589 © 2018 American College of Neuropsychopharmacology. All rights reserved 0893-133X/18 www.neuropsychopharmacology.org Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation 1 2 2 2 3 4 William R Kem , Ann Olincy , Lynn Johnson , Josette Harris , Brandie D Wagner , Robert W Buchanan , 5 ,2 Uwe Christians and Robert Freedman* 1 2 Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA; Department of Psychiatry F-546, 3 University of Colorado School of Medicine, Aurora, CO, USA; Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, 4 CO, USA; Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; 5 Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4- dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. -
Ca2+ and Brain-Derived Neurotrophic Factor (BDNF) in STC-1 Cells Jie Qian Virginia Commonwealth University
Virginia Commonwealth University VCU Scholars Compass Physiology and Biophysics Publications Dept. of Physiology and Biophysics 2015 Nicotine-Induced Effects on Nicotinic Acetylcholine Receptors (nAChRs), Ca2+ and Brain-Derived Neurotrophic Factor (BDNF) in STC-1 Cells Jie Qian Virginia Commonwealth University Shobha K. Mummalaneni Virginia Commonwealth University Reem M. Alkahtan Virginia Commonwealth University See next page for additional authors Follow this and additional works at: http://scholarscompass.vcu.edu/phis_pubs Part of the Medicine and Health Sciences Commons Copyright: © 2016 Qian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Downloaded from http://scholarscompass.vcu.edu/phis_pubs/54 This Article is brought to you for free and open access by the Dept. of Physiology and Biophysics at VCU Scholars Compass. It has been accepted for inclusion in Physiology and Biophysics Publications by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Authors Jie Qian, Shobha K. Mummalaneni, Reem M. Alkahtan, Sunila Mahavadi, Karnam S. Murthy, John R. Grider, and Vijay Lyall This article is available at VCU Scholars Compass: http://scholarscompass.vcu.edu/phis_pubs/54 RESEARCH ARTICLE Nicotine-Induced Effects on Nicotinic Acetylcholine Receptors (nAChRs), Ca2+ and Brain-Derived Neurotrophic