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Effects of Chronic Systemic Low-Impact Ampakine Treatment On
Biomedicine & Pharmacotherapy 105 (2018) 540–544 Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Effects of chronic systemic low-impact ampakine treatment on neurotrophin T expression in rat brain ⁎ Daniel P. Radin , Steven Johnson, Richard Purcell, Arnold S. Lippa RespireRx Pharmaceuticals, Inc., 126 Valley Road, Glen Rock, NJ, 07452, United States ARTICLE INFO ABSTRACT Keywords: Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric Ampakine diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating BDNF their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in Cognitive enhancement response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a LTP clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive Neurotrophin allosteric modulators of AMPA-type glutamate receptors. Currently, they are being developed to prevent opioid- NGF induced respiratory depression without sacrificing the analgesic properties of the opioids. In addition, these molecules increase neuronal activity and have been shown to restore age-related deficits in LTP in aged rats. In the current study, we examined whether two different ampakines could increase levels of BDNF and NGF at doses that are active in behavioral measures of cognition. Results demonstrate that ampakines CX516 and CX691 induce differential increases in neurotrophins across several brain regions. Notable increases in NGF were ob- served in the dentate gyrus and piriform cortex while notable BDNF increases were observed in basolateral and lateral nuclei of the amygdala. -
Performance Enhancement at the Cost of Potential Brain Plasticity: Neural Ramifications of Nootropic Drugs in the Healthy Developing Brain
REVIEW ARTICLE published: 13 May 2014 SYSTEMS NEUROSCIENCE doi: 10.3389/fnsys.2014.00038 Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain Kimberly R. Urban 1 and Wen-Jun Gao 2* 1 Department of Psychology, University of Delaware, Newark, DE, USA 2 Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA Edited by: Cognitive enhancement is perhaps one of the most intriguing and controversial Mikhail Lebedev, Duke University, topics in neuroscience today. Currently, the main classes of drugs used as potential USA cognitive enhancers include psychostimulants (methylphenidate (MPH), amphetamine), Reviewed by: Kimberly Simpson, University of but wakefulness-promoting agents (modafinil) and glutamate activators (ampakine) are Mississippi Medical Center, USA also frequently used. Pharmacologically, substances that enhance the components Christopher R. Madan, University of of the memory/learning circuits—dopamine, glutamate (neuronal excitation), and/or Alberta, Canada norepinephrine—stand to improve brain function in healthy individuals beyond their *Correspondence: baseline functioning. In particular, non-medical use of prescription stimulants such as Wen-Jun Gao, Department of Neurobiology and Anatomy, Drexel MPH and illicit use of psychostimulants for cognitive enhancement have seen a recent University College of Medicine, rise among teens and young adults in schools and college campuses. However, this 2900 Queen Lane, Philadelphia, PA enhancement likely comes with a neuronal, as well as ethical, cost. Altering glutamate 19129, USA function via the use of psychostimulants may impair behavioral flexibility, leading to e-mail: [email protected] the development and/or potentiation of addictive behaviors. Furthermore, dopamine and norepinephrine do not display linear effects; instead, their modulation of cognitive and neuronal function maps on an inverted-U curve. -
General Anesthesia and Altered States of Arousal: a Systems Neuroscience Analysis
General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Brown, Emery N., Patrick L. Purdon, and Christa J. Van Dort. “General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis.” Annual Review of Neuroscience 34, no. 1 (July 21, 2011): 601–628. As Published http://dx.doi.org/10.1146/annurev-neuro-060909-153200 Publisher Annual Reviews Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/86331 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ NIH Public Access Author Manuscript Annu Rev Neurosci. Author manuscript; available in PMC 2012 July 06. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Annu Rev Neurosci. 2011 ; 34: 601–628. doi:10.1146/annurev-neuro-060909-153200. General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis Emery N. Brown1,2,3, Patrick L. Purdon1,2, and Christa J. Van Dort1,2 Emery N. Brown: [email protected]; Patrick L. Purdon: [email protected]; Christa J. Van Dort: [email protected] 1Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 2Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 3Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Abstract Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. -
Neuroenhancement in Healthy Adults, Part I: Pharmaceutical
l Rese ca arc ni h li & C f B o i o l e Journal of a t h n Fond et al., J Clinic Res Bioeth 2015, 6:2 r i c u s o J DOI: 10.4172/2155-9627.1000213 ISSN: 2155-9627 Clinical Research & Bioethics Review Article Open Access Neuroenhancement in Healthy Adults, Part I: Pharmaceutical Cognitive Enhancement: A Systematic Review Fond G1,2*, Micoulaud-Franchi JA3, Macgregor A2, Richieri R3,4, Miot S5,6, Lopez R2, Abbar M7, Lancon C3 and Repantis D8 1Université Paris Est-Créteil, Psychiatry and Addiction Pole University Hospitals Henri Mondor, Inserm U955, Eq 15 Psychiatric Genetics, DHU Pe-psy, FondaMental Foundation, Scientific Cooperation Foundation Mental Health, National Network of Schizophrenia Expert Centers, F-94000, France 2Inserm 1061, University Psychiatry Service, University of Montpellier 1, CHU Montpellier F-34000, France 3POLE Academic Psychiatry, CHU Sainte-Marguerite, F-13274 Marseille, Cedex 09, France 4 Public Health Laboratory, Faculty of Medicine, EA 3279, F-13385 Marseille, Cedex 05, France 5Inserm U1061, Idiopathic Hypersomnia Narcolepsy National Reference Centre, Unit of sleep disorders, University of Montpellier 1, CHU Montpellier F-34000, Paris, France 6Inserm U952, CNRS UMR 7224, Pierre and Marie Curie University, F-75000, Paris, France 7CHU Carémeau, University of Nîmes, Nîmes, F-31000, France 8Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany *Corresponding author: Dr. Guillaume Fond, Pole de Psychiatrie, Hôpital A. Chenevier, 40 rue de Mesly, Créteil F-94010, France, Tel: (33)178682372; Fax: (33)178682381; E-mail: [email protected] Received date: January 06, 2015, Accepted date: February 23, 2015, Published date: February 28, 2015 Copyright: © 2015 Fond G, et al. -
Ampakines Potentiate the Corticostriatal Pathway to Reduce Acute and Chronic Pain Fei Zeng1,2, Qiaosheng Zhang2, Yaling Liu2, Guanghao Sun2, Anna Li2, Robert S
Zeng et al. Mol Brain (2021) 14:45 https://doi.org/10.1186/s13041-021-00757-y RESEARCH Open Access AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain Fei Zeng1,2, Qiaosheng Zhang2, Yaling Liu2, Guanghao Sun2, Anna Li2, Robert S. Talay2 and Jing Wang2,3* Abstract The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specif- cally, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and afective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifcally potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. How- ever, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-noci- ceptive efects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the efect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostri- atal circuit as an important analgesic approach. -
Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction?
Pharmaceuticals 2014, 7, 29-45; doi:10.3390/ph7010029 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction? Lucas R. Watterson 1,* and M. Foster Olive 1,2 1 Department of Psychology, Behavioral Neuroscience Area, Arizona State University, Tempe, AZ 85287, USA 2 Interdisciplinary Graduate Program in Neuroscience, Arizona State University, Tempe, AZ 85287, USA * Author to whom correspondence should be addressed; E-Mail:[email protected]; Tel.: +1-480-965-2573. Received: 28 October 2013; in revised form: 13 December 2013 / Accepted: 24 December 2013 / Published: 30 December 2013 Abstract: Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications. -
Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory
4930 • The Journal of Neuroscience, May 4, 2016 • 36(18):4930–4939 Behavioral/Cognitive Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory Abigail Benn, Gareth R. I. Barker, Sarah A. Stuart, XEva v. L. Roloff, XAnja G. Teschemacher, E. Clea Warburton, and Emma S. J. Robinson School of Physiology, Pharmacology, and Neuroscience, Faculty of Biomedical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the poten- tial to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically. Selective stimulation of glutamatergic neurons during the online maintenance of information enhanced associative recognition memory in normal animals. This cognitive enhancing effect was replicated by local infusions of the AMPAkine CX516, but not CX546, which differ in their effects on EPSPs. This suggests that enhancing the amplitude, but not the duration, of excitatory synaptic currents improves memory performance. Increasing glutamate release through infusions of the mGluR7 presynaptic receptor antagonist MMPIP had no effect on performance. Key words: AMPAkine; optogenetics; prefrontal cortex; rat; recognition memory Significance Statement These results provide new mechanistic information that could guide the targeting of future cognitive enhancers. Our work suggests that improved associative-recognition memory can be achieved by enhancing endogenous glutamatergic neuronal ac- tivity selectively using an optogenetic approach. We build on these observations to recapitulate this effect using drug treatments thatenhancetheamplitudeofEPSPs;however,drugsthatalterthedurationoftheEPSPorincreaseglutamatereleaselackefficacy. -
Enhancement of Ampakine-Induced
(19) & (11) EP 1 715 863 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/445 (2006.01) A61K 31/40 (2006.01) 09.05.2012 Bulletin 2012/19 A61K 31/4525 (2006.01) A61K 45/06 (2006.01) (21) Application number: 05712023.0 (86) International application number: PCT/US2005/002372 (22) Date of filing: 26.01.2005 (87) International publication number: WO 2005/072345 (11.08.2005 Gazette 2005/32) (54) ENHANCEMENT OF AMPAKINE-INDUCED FACILITATION OF SYNAPTIC RESPONSES BY CHOLINESTERASE INHIBITORS VERBESSERUNG DER DURCH AMPAKINE INDUZIERTEN ERLEICHTERUNG VON SYNAPTISCHEN REAKTIONEN DURCH CHOLINESTERASE-INHIBITOREN RENFORCEMENT DE LA FACILITATION INDUITE PAR AMPAKINE DES REPONSES SYNAPTIQUES PAR LES INHIBITEURS DE LA CHOLINESTERASE (84) Designated Contracting States: (74) Representative: Baldock, Sharon Claire AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Boult Wade Tennant HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR Verulam Gardens 70 Gray’s Inn Road (30) Priority: 26.01.2004 US 539422 P London WC1X 8BT (GB) (43) Date of publication of application: (56) References cited: 02.11.2006 Bulletin 2006/44 EP-A- 1 203 584 US-A- 5 747 492 US-B2- 6 689 795 (73) Proprietors: • CORTEX PHARMACEUTICALS, INC. • JOHNSON STEVEN A ET AL: "Randomized, Irvine, CA 92618 (US) double-blind, placebo-controlled international • The Regents of The University of California clinical trial of the Ampakine CX516 in elderly Oakland, CA 94607-5200 (US) participants with mild cognitive impairment. -
Ampakine CX1942 Attenuates Opioid-Induced Respiratory Depression and Corrects the Hypoxaemic Effects of Etorphine in Immobilized Goats (Capra Hircus)
Ampakine CX1942 attenuates opioid-induced respiratory depression and corrects the hypoxaemic effects of etorphine in immobilized goats (Capra hircus) Anna J Haw*, Leith CR Meyer*,†, John J Greer‡ & Andrea Fuller*,† * Brain Function Research Group, Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Parktown, South Africa †Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa ‡Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada Correspondence: Anna J Haw, Brain Function Research Group, Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa. E-mail: [email protected] Abstract Objectives: To determine whether CX1942 reverses respiratory depression in etorphine- immobilized goats, and to compare its effects with those of doxapram hydrochloride. Study design: A prospective, crossover experimental trial conducted at 1753 m.a.s.l. Animals: Eight adult female Boer goats (Capra hircus) with a mean ± standard deviation mass of 27.1 ± 1.6 kg. Methods: Following immobilization with 0.1 mg kg−1 etorphine, goats received one of doxapram, CX1942 or sterile water intravenously, in random order in three trials. Respiratory rate, ventilation and tidal volume were measured continuously. Arterial blood samples for the determination of PaO2, PaCO2, pH and SaO2 were taken 2 minutes before and then at 5 minute intervals after drug administration for 25 minutes. Results: Doxapram corrected etorphine-induced respiratory depression but also led to arousal and hyperventilation at 2 minutes after its administration, as indicated by the low −1 PaCO2 (27.8 ± 4.5 mmHg) and ventilation of 5.32 ± 5.24 L minute above pre-immobilization values. -
Pharmacological Modulation of Hypoxia-Induced Respiratory Neuroplasticity ⁎ Sara Turnera,C, Kristi Streetera,C, John Greerb, Gordon S
Respiratory Physiology & Neurobiology xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol Pharmacological modulation of hypoxia-induced respiratory neuroplasticity ⁎ Sara Turnera,c, Kristi Streetera,c, John Greerb, Gordon S. Mitchella,c, David D. Fullera,c, a University of Florida, College of Public Health and Health Professions, McKnight Brain Institute, Department of Physical Therapy, PO Box 100154, 100 S. Newell Dr, Gainesville, FL 32610, United States b Department of Physiology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada c Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, FL 32610, United States ARTICLE INFO ABSTRACT Keywords: Hypoxia elicits complex cell signaling mechanisms in the respiratory control system that can produce long- Pharmacology lasting changes in respiratory motor output. In this article, we review experimental approaches used to elucidate Hypoxia episodes signaling pathways associated with hypoxia, and summarize current hypotheses regarding the intracellular Signaling mechanisms signaling pathways evoked by intermittent exposure to hypoxia. We review data showing that pharmacological Breathing treatments can enhance neuroplastic responses to hypoxia. Original data are included to show that pharmaco- logical modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function can reveal a respiratory neuroplastic response to a single, brief hypoxic exposure in anesthetized mice. Coupling pharmacologic treatments with therapeutic hypoxia paradigms may have rehabilitative value following neu- rologic injury or during neuromuscular disease. Depending on prevailing conditions, pharmacologic treatments can enable hypoxia-induced expression of neuroplasticity and increased respiratory motor output, or potentially could synergistically interact with hypoxia to more robustly increase motor output. -
Muscarinic Receptor Occupancy and Cognitive Impairment: a PET Study with [11C]( + )3-MPB and Scopolamine in Conscious Monkeys
Neuropsychopharmacology (2011) 36, 1455–1465 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 $32.00 www.neuropsychopharmacology.org Muscarinic Receptor Occupancy and Cognitive Impairment: A PET Study with [11C]( + )3-MPB and Scopolamine in Conscious Monkeys 1 2 2 2 3 Shigeyuki Yamamoto , Shingo Nishiyama , Masahiro Kawamata , Hiroyuki Ohba , Tomoyasu Wakuda , Nori Takei1, Hideo Tsukada2 and Edward F Domino4 1 Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 2 3 Japan; Central Research Laboratory, Hamamatsu Photonics KK, Hirakuchi, Hamakita, Hamamatsu, Shizuoka, Japan; Department of Psychiatry 4 and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with 11 11 the mAChR radioligand N-[ C]methyl-3-piperidyl benzilate ([ C]( + )3-MPB). The scan sequence was pre-, 2, 6, 24, and 48 h post- intramuscular administration of scopolamine in doses of 0.01 and 0.03 mg/kg. Occupancy levels of mAChR were maximal 2 h post- scopolamine in cortical regions innervated primarily by the basal forebrain, thalamus, and brainstem, showing that mAChR occupancy levels were 43–59 and 65–89% in doses of 0.01 and 0.03 mg/kg, respectively. In addition, dose-dependent impairment of working memory performance was measured 2 h after scopolamine. -
The Glutamate Receptor Ion Channels
0031-6997/99/5101-0007$03.00/0 PHARMACOLOGICAL REVIEWS Vol. 51, No. 1 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. The Glutamate Receptor Ion Channels RAYMOND DINGLEDINE,1 KARIN BORGES, DEREK BOWIE, AND STEPHEN F. TRAYNELIS Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia This paper is available online at http://www.pharmrev.org I. Introduction ............................................................................. 8 II. Gene families ............................................................................ 9 III. Receptor structure ...................................................................... 10 A. Transmembrane topology ............................................................. 10 B. Subunit stoichiometry ................................................................ 10 C. Ligand-binding sites located in a hinged clamshell-like gorge............................. 13 IV. RNA modifications that promote molecular diversity ....................................... 15 A. Alternative splicing .................................................................. 15 B. Editing of AMPA and kainate receptors ................................................ 17 V. Post-translational modifications .......................................................... 18 A. Phosphorylation of AMPA and kainate receptors ........................................ 18 B. Serine/threonine phosphorylation of NMDA receptors ..................................