Phenotypic Characterization of an Α4 Neuronal Nicotinic Acetylcholine Receptor Subunit Knock-Out Mouse

Total Page:16

File Type:pdf, Size:1020Kb

Phenotypic Characterization of an Α4 Neuronal Nicotinic Acetylcholine Receptor Subunit Knock-Out Mouse The Journal of Neuroscience, September 1, 2000, 20(17):6431–6441 ␣ Phenotypic Characterization of an 4 Neuronal Nicotinic Acetylcholine Receptor Subunit Knock-Out Mouse Shelley A. Ross,1 John Y. F. Wong,1 Jeremiah J. Clifford,3 Anthony Kinsella,4 Jim S. Massalas,1 Malcolm K. Horne,1 Ingrid E. Scheffer,1,5 Ismail Kola,2 John L. Waddington,3 Samuel F. Berkovic,5 and John Drago1 1Neurosciences Group, Monash University Department of Medicine and 2Institute of Reproduction and Development, Monash Medical Centre, Clayton, Victoria, 3168, Australia, 3Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland, 4Department of Mathematics, Dublin Institute of Technology, Dublin 8, Ireland, and 5Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, 3084, Australia Neuronal nicotinic acetylcholine receptors (nAChR) are present in tions; conversely, heightened levels of behavioral topographies in high abundance in the nervous system (Decker et al., 1995). Mt were reduced by nicotine in the late phase of the unhabitu- There are a large number of subunits expressed in the brain that ated condition. Ligand autoradiography confirmed the lack of combine to form multimeric functional receptors. We have gen- high-affinity binding to radiolabeled nicotine, cytisine, and epiba- ␣ erated an 4 nAChR subunit knock-out line and focus on defining tidine in the thalamus, cortex, and caudate putamen, although the behavioral role of this receptor subunit. Homozygous mutant binding to a number of discrete nuclei remained. The study ␣ mice (Mt) are normal in size, fertility, and home-cage behavior. confirms the pivotal role played by the 4 nAChR subunit in the Spontaneous unconditioned motor behavior revealed an etho- modulation of a number of constituents of the normal mouse gram characterized by significant increases in several topogra- ethogram and in anxiety as assessed using the plus-maze. Fur- phies of exploratory behavior in Mt relative to wild-type mice (Wt) thermore, the response of Mt to nicotine administration suggests over the course of habituation to a novel environment. Further- that persistent nicotine binding sites in the habenulo- more, the behavior of Mt in the elevated plus-maze assay was interpeduncular system are sufficient to modulate motor activity consistent with increased basal levels of anxiety. In response to in actively exploring mice. ␣ nicotine, Wt exhibited early reductions in a number of behavioral Key words: 4 ; nicotinic receptor; homologous recombination; topographies, under both unhabituated and habituated condi- anxiety; knock-out; behavioral topography Nicotine is one of the most widely consumed psychoactive drugs Despite detailed characterization of nAChR subunits at the and exerts a number of pharmacological actions in the CNS and molecular level, not much is known about the in vivo functional PNS (Decker et al., 1995). Neuronal nicotinic acetylcholine recep- role of individual subunits. Most nAChR ligands show similar tors (nAChR) constitute a heterogenous family of pentameric patterns of high-affinity labeling that resembles the distribution of oligomers with contributions from 11 subunits (Le Novere and ␣ /␤ subunits. A number of nAChR agonists that bind to the ␣ /␤ ␣ ␣ ␣ 4 2 4 2 Changeux, 1995). Five types of subunits ( 2– 6) and three types receptor configuration in vitro are known to have an effect on ␤ ␤ ␤ ␣ ␤ of subunits ( 2– 4) permit combinations of and type subunits anxiety (Pomerleau, 1986; Gilbert et al., 1989; Brioni et al., 1993), to form a number of functional receptors with subunits of two or attention (Brioni et al., 1997), and antinociception (Tripathi et al., more different types (Changeux et al., 1998), whereas subunits 1982; Damaj et al., 1998), implicating the ␣ /␤ receptor in the ␣ ␣ ␣ 4 2 7– 9 can form -bungarotoxin-sensitive homopentameric recep- mediation of a number of physiological processes. Analysis of an tors (Corringer et al., 1995). The topography of nAChR subunits ␣ independently generated line of 4 nAChR subunit knock-out mice varies (Deneris et al., 1989; Duvoisin et al., 1989; Wada et al., 1989, (Marubio et al., 1999) validated the significant role played by this 1990; Hill et al., 1993; Elgoyhen et al., 1994; Court and Perry, 1995; receptor subunit in nociception. Loss of nicotinic binding sites and ␣ Le Novere et al., 1996; Brioni et al., 1997; Zoli et al., 1998), with 4 a decrease of nAChR protein expression has been shown in pa- ␤ and 2 transcripts being found in a large number of CNS nuclei, tients with Alzheimer’s disease and patients with Parkinson’s dis- ␣ ␣ ␣ ␣ ␤ ␤ whereas 2, 3, 5, 6, 3, and 4 mRNAs are restricted to a few ␣ ␤ ease with cognitive dysfunction (Giacobini, 1991; Brioni et al., cholinergic pathways, which also express 4 and 2. ␣ 1997). Furthermore, several mutations in the 4 nAChR subunit have been identified in autosomal dominant nocturnal frontal lobe Received Jan. 10, 2000; revised June 9, 2000; accepted June 14, 2000. epilepsy (Steinlein et al., 1995, 1997). The large number of subunits This work is supported in part by the National Health and Medical Research suggests a potential for considerable diversity in nAChR func- Council of Australia (NHMRC), the Australian Commonwealth Department of Vet- tion(s). Defining the specific role played by individual subunits in eran’s Affairs, and an unrestricted educational grant from Parke-Davis (Australia). S.R. was supported by a Peter Bladin Scholarship from the Epilepsy Society of determining spontaneous motor behavior and responses to drug Australia. J.D. is a Monash University Logan Research Fellow. J.J.C. was supported challenge will be aided by ongoing analysis of nAChR subunit gene by the NHMRC Brain Network into Mental Health Diseases. J.L.W. and J.J.C. are knock-out mice (Picciotto et al., 1995; Orr-Urtreger et al., 1997; supported by a Galen Fellowship from the Irish Brain Research Foundation, the Marubio et al., 1999; Xu et al., 1999). Higher Education Authority of Ireland, and the Royal College of Surgeons in Ireland. We thank Prof. Bevyn Jarrott (Department of Pharmacology, Monash University) for Nicotine is known to reduce anxiety in both chronic smokers the gift of iodinated ␣-bungarotoxin. We also thank Dr. Ian Simpson for his help with (Gilbert, 1979; Pomerleau, 1986; Gilbert et al., 1989) and nonsmok- organ histology. ers (Hutchinson and Emley, 1973). Anxiolytic-like effects of nico- J.Y.F.W. and J.J.C. contributed equally to this work. tine and a select number of neuronal nicotinic receptor agonists Correspondence should be addressed to Dr. J. Drago, Department of Medicine, 5th Floor E Block, Monash Medical Centre, Clayton Road, Clayton, Victoria, 3168, have also been documented in experimental animals (Costall et al., Australia. E-mail: [email protected]. 1989; Brioni et al., 1993; Cao et al., 1993). The differential behav- Copyright © 2000 Society for Neuroscience 0270-6474/00/206431-11$15.00/0 ioral profile of neuronal nicotinic agonists implies that the anxio- • ␣ 6432 J. Neurosci., September 1, 2000, 20(17):6431–6441 Ross et al. 4 Neuronal Nicotinic Receptor Knock-Out Mice Figure 1. Construction of targeting vector and Southern blot analysis of ES clones. Representation of the genomic map of ␣ the 4 nAChR gene (A), the targeting vector (B), and the expected allelic disruption after homologous recombination (C). The restriction sites shown are abbreviated as follows: N, NotI; H, HindIII; Bg, BglII; Sc, ScaI; X, XhoI; E, EcoRI; B, BamHI. NEO represents the neomycin phosphotransferase resistance gene, and TK represents the thymidine kinase gene. The origin of the probes used for homologous recom- bination screening are also shown. Probe pE1 is a HindIII- BglII fragment used to confirm 5Ј recombination, and probe pE2 is a HindIII-BamHI fragment used for confirmation of 3Ј recombination. D shows the Southern blot of HindIII- digested ES cell genomic DNA probed with pE1 (Wt allele is 6 kb, and the recombinant allele is 4.2 kb), showing correctly targeted clones (C3, C44, C55, and C59); C67 is a randomly selected nontargeted clone. E shows the Southern blot of BamHI-digested ES cell genomic DNA probed with pE2; the Wt allele is 12 kb, and the recombinant allele is 2.5 kb (clones C3, C44, C55, and C59 are correctly targeted). F shows a Southern blot of a BamHI-digested probed with a NEO- specific probe. Clones C3, C44, C55, and C59 have a single band at the expected size of 8 kb, confirming a single inser- tion event in all the clones examined. lytic actions of nicotine may be mediated by a specific subunit by probing a BamHI Southern blot with a neomycin phosphotransferase ␣ (NEO) gene cDNA probe (Fig. 1). Four recombinants were identified by configuration of the nAChR. We generated an 4 nAChR knock- ␣ Southern blotting (Fig. 1), one of which (C3) was injected into BALB/C out line to test the hypothesis that mice lacking 4 nAChR subunits blastocysts, and chimeras were generated. Chimeras were mated with CF1 would show behavioral features consistent with heightened basal mice, and a single heterozygous mouse (Hz) was obtained. The Hz founder levels of anxiety. was used to generate the entire colony by subsequent crossing with C57/ BL6 mice. Hz progeny, obtained after two backcrosses with C57/BL6 mice, MATERIALS AND METHODS were mated to establish a number of mutant mice (Mt) mating pairs and wild-type mice (Wt) mating pairs. All Mt mice used in this study were Animals. All procedures involving the use of live animals conformed to the therefore derived from Mt intermatings, and all Wt mice were derived National Health and Medical Research Council (NHMRC) code of from Wt intermatings. Maximal diversity in the genetic background was practice. maintained by randomly interchanging breeders within a given genotype. Cloning. A 1.0 kb cDNA probe encoding the putative second transmem- ϭ ϭ ϭ brane domain of the ␣ nAChR receptor subunit was cloned by PCR Tissue preparation.
Recommended publications
  • PRODUCT INFORMATION ABT-594 Item No
    PRODUCT INFORMATION ABT-594 Item No. 22822 CAS Registry No.: 203564-54-9 Formal Name: 5-[(2R)-2-azetidinylmethoxy]-2- H chloro-pyridine, monohydrochloride N Synonyms: Ebanicline, Tebanicline O MF: C9H11ClN2O • HCl FW: 235.1 N Purity: ≥95% Cl Supplied as: A solid • HCl Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures ABT-594 is supplied as a solid. A stock solution may be made by dissolving the ABT-594 in the solvent of choice. ABT-594 is soluble in the organic solvent DMSO, which should be purged with an inert gas. Description ABT-594 is a potent agonist of neuronal α4β2 subunit-containing nicotinic acetylcholine receptors 1 (nAChRs; Ki = 37 pM in a radioligand binding assay). It is selective for neuronal nAChRs over neuromuscular α1β1δγ subunit-containing nAChRs (Ki = 10,000 nM), α1B-, α2B-, and α2C-adrenergic receptors (Kis = 890, 597, and 342 nM, respectively), and 70 other receptors, enzymes, and transporters 86 + (Kis = >1,000 nM) in radioligand binding assays. ABT-594 induces [ Rb ] efflux in K177 cells transfected with human neuronal α4β2 subunit-containing nAChRs (EC50 = 140 nM). In vivo, ABT-594 (0.05 and 0.01 mg/kg, s.c.) increases latency to paw withdrawal in a hot-plate test in rats.2 It also induces hypothermia, seizures, and an increase in blood pressure. References 1. Donnelly-Roberts, D.L., Puttfarcken, P.S., Kuntzweiler, T.A., et al. ABT-594 [(R)-5-(2-azetidinylmethoxy)- 2-chloropyridine]: A novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I.
    [Show full text]
  • Chemicals in the Fourth Report and Updated Tables Pdf Icon[PDF
    Chemicals in the Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 CDC’s Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 provides exposure data on the following chemicals or classes of chemicals. The Updated Tables contain cumulative data from national samples collected beginning in 1999–2000 and as recently as 2015-2016. Not all chemicals were measured in each national sample. The data tables are available at https://www.cdc.gov/exposurereport. An asterisk (*) indicates the chemical has been added since publication of the Fourth National Report on Human Exposure to Environmental Chemicals in 2009. Adducts of Hemoglobin Acrylamide Formaldehyde* Glycidamide Tobacco Alkaloids and Metabolites Anabasine* Anatabine* Cotinine Cotinine-n-oxide* Hydroxycotinine* Trans-3’-hydroxycotinine* 1-(3-Pyridyl)-1-butanol-4-carboxylic acid* Nicotine* Nicotine-N’-oxide* Nornicotine* Tobacco-Specific Nitrosamines (TSNAs) N’-Nitrosoanabasine (NAB)* N’-Nitrosoanatabine (NAT)* N’-Nitrosonornicotine (NNN)* Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL)* Volatile N-nitrosamines (VNAs) N-Nitrosodiethylamine (NDEA)* N-Nitrosoethylmethylamine (NMEA)* N-Nitrosomorpholine (NMOR)* N-Nitrosopiperidine (NPIP)* N-Nitrosopyrrolidine (NPYR)* Disinfection By-Products Bromodichloromethane Dibromochloromethane Tribromomethane (Bromoform) Trichloromethane (Chloroform) Personal Care and Consumer Product Chemicals and Metabolites Benzophenone-3 Bisphenol A Bisphenol F* Bisphenol
    [Show full text]
  • Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence
    Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence Christie D. Fowler, Jill R. Turner, and M. Imad Damaj Contents 1 Introduction 2 Basic Neurocircuitry of Nicotine Addiction 3 Role of Nicotinic Receptors in Nicotine Dependence and Brain Function 4 Modulatory Factors That Influence nAChR Expression and Signaling 5 Genomics and Genetics of Nicotine Dependence 5.1 Overview 5.2 Human and Animal Genetic Studies 5.3 Transcriptionally Adaptive Changes 6 Other Constituents in Nicotine and Tobacco Products Mediating Dependence 7 Therapeutic Approaches for Tobacco and Nicotine Dependence 7.1 Nicotine Replacement Therapies 7.2 Varenicline and Bupropion 7.3 Novel Approaches 8 Conclusion References Abstract Tobacco dependence is a leading cause of preventable disease and death world- wide. Nicotine, the main psychoactive component in tobacco cigarettes, has also C. D. Fowler Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA J. R. Turner Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA M. Imad Damaj (*) Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA Translational Research Initiative for Pain and Neuropathy at VCU, Richmond, VA, USA e-mail: [email protected] # Springer Nature Switzerland AG 2019 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2019_252 C. D. Fowler et al. been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms under- lying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field’s current understanding of nicotine’s actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence.
    [Show full text]
  • (19) United States (12) Patent Application Publication (10) Pub
    US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist.
    [Show full text]
  • NINDS Custom Collection II
    ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC
    [Show full text]
  • Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna
    Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna (Junior-Biochemistry major) Faculty Advisor: Dr. Thomas Montgomery Duquesne University- Bayer School of Natural Sciences 1 Abstract: Epibatidine is a naturally toxic chemical found in the secretion of poison dart frogs. Given its structural similarities to the compound nicotine epibatidine binds strongly to nicotine receptors in the central nervous system (CTS). Epibatidine’s bioactivity arises from its unique geometry which allows it to bind to the α4β2 subunit in the nicotinic receptor. This triggers an analgesic effect without a release of dopamine, differentiating its activity from opioids. Prior efforts towards synthesizing epibatidine and its analogs have involved many steps making them untenable for pharmaceutical use. By using computational and experimental methods to study the mechanism for an interrupted Polonovski [3+2] cycloaddition which will give direct access to the epibatidine core motif. By synthesizing strategic derivatives of epibatidine through this route we will investigate opioid alternatives which lack many of their addictive qualities. Background: Epibatidine is a toxic alkaloid that is isolated from the skin of poison dart tree frog Epipedobates tricolor, secretions from the frog are used by indigenous tribes in darts for hunting.1 The chemical structure was established in 1992 using NMR spectroscopy (proton NMR).2 Epibatidine possesses significant medicinal properties, it functions as an analgesic agent by binding to the nicotinic acetylcholine receptors (nAChRs) instead of the opioid receptors.3 Moreover it displays an affinity for said receptors that is 100- to 200-fold higher than nicotine. The alkaloid interacts with Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and are expressed central and peripherally.
    [Show full text]
  • Biomarkers of Exposure Among Adult Smokeless Tobacco Users in the Population Assessment of Tobacco and Health Study (Wave 1, 2013-14)
    Author Manuscript Published OnlineFirst on January 27, 2020; DOI: 10.1158/1055-9965.EPI-19-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Biomarkers of Exposure among Adult Smokeless Tobacco Users in the Population Assessment of Tobacco and Health Study (Wave 1, 2013-14) Running Title: Biomarkers of Exposure in PATH Study Smokeless Tobacco Users Yu-Ching Cheng1, Carolyn M. Reyes-Guzman1,2, Carol H. Christensen1, Brian L. Rostron1, Kathryn C. Edwards3, Lanqing Wang4, Jun Feng4, Jeffery M. Jarrett4, Cynthia D. Ward 4, Baoyun Xia4, Heather L. Kimmel5, Kevin Conway5, Carmine Leggett1, Kristie Taylor3, Charlie Lawrence3, Ray Niaura6, Mark J. Travers7, Andrew Hyland7, Stephen S. Hecht8, Dorothy K. Hatsukami8, Maciej L. Goniewicz7, Nicolette Borek1, Benjamin C. Blount4, Dana M. van Bemmel1 1Center for Tobacco Products, Food and Drug Administration, MD, USA, 2National Cancer Institute, National Institutes of Health, MD, USA, 3Westat, MD, USA, 4US Centers for Disease Control and Prevention, USA, 5National Institute on Drug Abuse, National Institutes of Health, MD, USA, 6New York University College of Global Public Health, NY, USA, 7Roswell Park Cancer Institute, NY, USA, 8University of Minnesota, Masonic Cancer Center, USA. Key Words: biomarkers of exposure, smokeless tobacco Corresponding author: Yu-Ching Cheng, PhD 11785 Beltsville Drive, RM 8321 Beltsville, MD 20705 [email protected] 240-402-5957 1 Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 27, 2020; DOI: 10.1158/1055-9965.EPI-19-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • JPET #226803 Title Page Effects of Nicotinic Acetylcholine Receptor
    JPET Fast Forward. Published on September 10, 2015 as DOI: 10.1124/jpet.115.226803 This article has not been copyedited and formatted. The final version may differ from this version. 1 JPET #226803 Title Page Effects of nicotinic acetylcholine receptor agonists in assays of acute pain-stimulated and pain- depressed behaviors in rats Kelen. C. Freitas, F. Ivy Carroll, and S. Stevens Negus Downloaded from Department of Pharmacology and Toxicology, Virginia Commonwealth University, jpet.aspetjournals.org Richmond VA, USA Research Triangle Institute, Research Triangle Park, NC, USA at ASPET Journals on September 26, 2021 JPET Fast Forward. Published on September 10, 2015 as DOI: 10.1124/jpet.115.226803 This article has not been copyedited and formatted. The final version may differ from this version. 2 JPET #226803 Running Title Page Effects of nicotinic drugs on pain-depressed behavior Address correspondence to: Kelen Freitas, Department of Pharmacology and Toxicology, Downloaded from Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298. Telephone: (804) 828-3158 Fax: (804) 828-2117 Email: [email protected] jpet.aspetjournals.org Number of text pages: 37 at ASPET Journals on September 26, 2021 Number of tables: 1 Number of figures: 6 Number of references: 76 Number of words in the abstract: 241 Number of words in the introduction: 746 Number of words in the discussion: 1.250 List of non-standard abbreviations nAChRs, nicotinic acetylcholine receptors DhβE, dihydro-ß-ertyroidine MD-354, Meta-chlorophenylguanidine Nicotine, (-)-nicotine hydrogen tartrate PNU 282987, N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide 5-I-A-85380, 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ICSS, intracranial self-stimulation MCR, maximum control rate %MCR, percentage of MCR ANOVA, analysis of variance JPET Fast Forward.
    [Show full text]
  • 7 Nicotinic Receptor Agonists
    CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central The Open Medicinal Chemistry Journal, 2010, 4, 37-56 37 Open Access 7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease Jun Toyohara, and Kenji Hashimoto* Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Abstract: Accumulating evidence suggests that 7 nicotinic receptors (7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that 7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that 7 nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that 7 nAChRs might play a key role in the amyloid- (A)-mediated pathology of AD, and that 7 nAChR agonists would be potential therapeutic drugs for A deposition in the brains of patients with AD. Interestingly, the altered expression of 7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective 7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of 7 nAChRs in the pathophysiology of these diseases and into the potential use of novel 7 nAChR agonists as therapeutic drugs. Keywords: 7 Nicotinic receptors, Cognition, Schizophrenia, Alzheimer’s disease.
    [Show full text]
  • With Amantadine
    CHARACTERIZATION OF RENAL CATIONIC DRUG TRANSPORT WITH AMANTADINE BY LEO T. Y. WONG A Tnrsrs SuslrrmEo ro rHE Fecurrv or Gn¡ouer¡ Sruoles tN P¿nr¡er- Fulrlnu¡NT oF THE R¡eutRptttn¡¡-rs ronr¡mD¡GREE oF DOCTOR OF PHIT,OSOPFTY Dpp¡nrue¡rr or PrunuacoI-ocy & THrn¡pEUTrcs Facurrv orMeotcl¡¡¡ UNrvensrrv on M¡Nrros¿ WrNNrno, Maì¡rrone R3E 0W3 C¡,N¡oe DecBr'an¡n 199L ¡.L Bibliothèque nationale E*E |'t:îå'o'Jo'"t du Canada Acquisitions and Direction des acquisitions et Bibliographic Services Branch des services bibliographiques 395 Wellington Street 395, rue Wellington Ottawa, Ontario Ottawa (Ontar¡o) K1A ON4 K1A ON4 Yout lile Volrc relërence Oú lile Nolrc relércnce The author has granted an L'auteur a accordé une licence irrevocable non-exclus¡ve licence irrévocable et non exclusive allowing the National Library of permettant à la Bibliothèque Canada to reproduce, loan, nationale du Canada de distribute or sell cop¡es of reproduire, prêter, distribuer ou his/her thesis by any means and vendre des copies de sa thèse in any form or format, making de quelque manière et sous this thesis available to interested quelque forme que ce soit pour persons. mettre des exemplaires de cette thèse à la disposition des personnes intéressées. The author retains ownership of L'auteur conserve la propriété du the copyright in his/her thesis. droit d'auteur qu¡ protège sa Neither the thesis nor substantial thèse. Ni la thèse ni des extraits extracts from it may be printed or substantiels de celle-ci ne otherwise reproduced without doivent être imprimés ou his/her permission.
    [Show full text]
  • Solanum Alkaloids and Their Pharmaceutical Roles: a Review
    Journal of Analytical & Pharmaceutical Research Solanum Alkaloids and their Pharmaceutical Roles: A Review Abstract Review Article The genus Solanum is treated to be one of the hypergenus among the flowering epithets. The genus is well represented in the tropical and warmer temperate Volume 3 Issue 6 - 2016 families and is comprised of about 1500 species with at least 5000 published Solanum species are endemic to the northeastern region. 1Department of Botany, India Many Solanum species are widely used in popular medicine or as vegetables. The 2Department of Botany, Trivandrum University College, India presenceregions. About of the 20 steroidal of these alkaloid solasodine, which is potentially an important starting material for the synthesis of steroid hormones, is characteristic of *Corresponding author: Murugan K, Plant Biochemistry the genus Solanum. Soladodine, and its glocosylated forms like solamargine, and Molecular Biology Lab, Department of Botany, solosonine and other compounds of potential therapeutic values. India, Email: Keywords: Solanum; Steroidal alkaloid; Solasodine; Hypergenus; Glocosylated; Trivandrum University College, Trivandrum 695 034, Kerala, Injuries; Infections Received: | Published: October 21, 2016 December 15, 2016 Abbreviations: TGA: Total Glycoalkaloid; SGA: Steroidal range of biological activities such as antimicrobial, antirheumatics, Glycoalkaloid; SGT: Sergeant; HMG: Hydroxy Methylglutaryl; LDL: Low Density Lipoprotein; ACAT: Assistive Context Aware Further, these alkaloids are of paramount importance in drug Toolkit; HMDM: Human Monocyte Derived Macrophage; industriesanticonvulsants, as they anti-inflammatory, serve as precursors antioxidant or lead molecules and anticancer. for the synthesis of many of the steroidal drugs which have been used CE: Cholesterol Ester; CCl4: Carbon Tetrachloride; 6-OHDA: 6-hydroxydopamine; IL: Interleukin; TNF: Tumor Necrosis Factor; DPPH: Diphenyl-2-Picryl Hydrazyl; FRAP: Fluorescence treatments.
    [Show full text]
  • Neuronal Nicotinic Receptors
    NEURONAL NICOTINIC RECEPTORS Dr Christopher G V Sharples and preparations lend themselves to physiological and pharmacological investigations, and there followed a Professor Susan Wonnacott period of intense study of the properties of nAChR- mediating transmission at these sites. nAChRs at the Department of Biology and Biochemistry, muscle endplate and in sympathetic ganglia could be University of Bath, Bath BA2 7AY, UK distinguished by their respective preferences for C10 and C6 polymethylene bistrimethylammonium Susan Wonnacott is Professor of compounds, notably decamethonium and Neuroscience and Christopher Sharples is a hexamethonium,5 providing the first hint of diversity post-doctoral research officer within the among nAChRs. Department of Biology and Biochemistry at Biochemical approaches to elucidate the structure the University of Bath. Their research and function of the nAChR protein in the 1970’s were focuses on understanding the molecular and facilitated by the abundance of nicotinic synapses cellular events underlying the effects of akin to the muscle endplate, in electric organs of the acute and chronic nicotinic receptor electric ray,Torpedo , and eel, Electrophorus . High stimulation. This is with the goal of affinity snakea -toxins, principallyaa -bungarotoxin ( - Bgt), enabled the nAChR protein to be purified, and elucidating the structure, function and subsequently resolved into 4 different subunits regulation of neuronal nicotinic receptors. designateda ,bg , and d .6 An additional subunit, e , was subsequently identified in adult muscle. In the early 1980’s, these subunits were cloned and sequenced, The nicotinic acetylcholine receptor (nAChR) arguably and the era of the molecular analysis of the nAChR has the longest history of experimental study of any commenced.
    [Show full text]