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Synaptic GABAA Receptor Clustering Without the 2 Subunit
The Journal of Neuroscience, July 30, 2014 • 34(31):10219–10233 • 10219 Cellular/Molecular ␥ Synaptic GABAA Receptor Clustering without the 2 Subunit Katalin Kerti-Szigeti, Zoltan Nusser, and X Mark D. Eyre Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1083, Hungary Rapid activation of postsynaptic GABAA receptors (GABAARs) is crucial in many neuronal functions, including the synchronization of neuronal ensembles and controlling the precise timing of action potentials. Although the ␥2 subunit is believed to be essential for the ␥ Ϫ/Ϫ postsynaptic clustering of GABAARs, synaptic currents have been detected in neurons obtained from 2 mice. To determine the role ␥ ␥ of the 2 subunit in synaptic GABAAR enrichment, we performed a spatially and temporally controlled 2 subunit deletion by injecting ␥ 77I Cre-expressing viral vectors into the neocortex of GABAAR 2 lox mice. Whole-cell recordings revealed the presence of miniature IPSCs in Cre ϩ layer 2/3 pyramidal cells (PCs) with unchanged amplitudes and rise times, but significantly prolonged decays. Such slowly decaying currents could be evoked in PCs by action potentials in presynaptic fast-spiking interneurons. Freeze-fracture replica immu- nogold labeling revealed the presence of the ␣1 and 3 subunits in perisomatic synapses of cells that lack the ␥2 subunit. Miniature IPSCs in Cre ϩ PCs were insensitive to low concentrations of flurazepam, providing a pharmacological confirmation of the lack of the ␥2 subunit. Receptors assembled from only ␣ subunits were unlikely because Zn 2ϩ did not block the synaptic currents. Pharmacological experiments indicated that the ␣␥3 receptor, rather than the ␣␦, ␣,or␣␥1 receptors, was responsible for the slowly decaying IPSCs.OurdatademonstratethepresenceofIPSCsandthesynapticenrichmentofthe␣1and3subunitsandsuggestthatthe␥3subunit ␥ is the most likely candidate for clustering GABAARs at synapses in the absence of the 2 subunit. -
2016 Bill No. CS for SB 1528 Ì460300XÎ460300
Florida Senate - 2016 PROPOSED COMMITTEE SUBSTITUTE Bill No. CS for SB 1528 460300 Ì460300XÎ 576-03397-16 Proposed Committee Substitute by the Committee on Appropriations (Appropriations Subcommittee on Criminal and Civil Justice) 1 A bill to be entitled 2 An act relating to illicit drugs; amending s. 893.02, 3 F.S.; defining terms; deleting a definition; revising 4 definitions; amending s. 893.03, F.S.; providing that 5 class designation is a way to reference scheduled 6 controlled substances; adding, deleting, and revising 7 the list of Schedule I controlled substances; revising 8 the list of Schedule III anabolic steroids; amending 9 s. 893.033, F.S.; adding, deleting, and revising the 10 list of precursor and essential chemicals; amending s. 11 893.0356, F.S.; defining the term “substantially 12 similar”; deleting the term “potential for abuse”; 13 requiring that a controlled substance analog be 14 treated as the highest scheduled controlled substance 15 of which it is an analog; amending s. 893.13, F.S.; 16 creating a noncriminal penalty for selling, 17 manufacturing, or delivering, or possessing with 18 intent to sell, manufacture, or deliver any unlawful 19 controlled substance in, on, or near an assisted 20 living facility; creating a criminal penalty for a 21 person 18 years of age or older who delivers to a 22 person younger than 18 years of age any illegal 23 controlled substance, who uses or hires a person 24 younger than 18 years of age in the sale or delivery 25 of such substance, or who uses a person younger than 26 18 years of age to assist in avoiding detection for 27 specified violations; deleting a criminal penalty for Page 1 of 197 2/12/2016 8:29:32 AM Florida Senate - 2016 PROPOSED COMMITTEE SUBSTITUTE Bill No. -
Texas Controlled Substances Act
HEALTH AND SAFETY CODE TITLE 6. FOOD, DRUGS, ALCOHOL, AND HAZARDOUS SUBSTANCES SUBTITLE C. SUBSTANCE ABUSE REGULATION AND CRIMES CHAPTER 481. TEXAS CONTROLLED SUBSTANCES ACT SUBCHAPTER A. GENERAL PROVISIONS Sec.A481.001.AASHORT TITLE. This chapter may be cited as the Texas Controlled Substances Act. Acts 1989, 71st Leg., ch. 678, Sec. 1, eff. Sept. 1, 1989. Sec.A481.002.AADEFINITIONS. In this chapter: (1)AA"Administer" means to directly apply a controlled substance by injection, inhalation, ingestion, or other means to the body of a patient or research subject by: (A)AAa practitioner or an agent of the practitioner in the presence of the practitioner; or (B)AAthe patient or research subject at the direction and in the presence of a practitioner. (2)AA"Agent" means an authorized person who acts on behalf of or at the direction of a manufacturer, distributor, or dispenser. The term does not include a common or contract carrier, public warehouseman, or employee of a carrier or warehouseman acting in the usual and lawful course of employment. (3)AA"Commissioner" means the commissioner of state health services or the commissioner 's designee. (4)AA"Controlled premises" means: (A)AAa place where original or other records or documents required under this chapter are kept or are required to be kept; or (B)AAa place, including a factory, warehouse, other establishment, or conveyance, where a person registered under this chapter may lawfully hold, manufacture, distribute, dispense, administer, possess, or otherwise dispose of a controlled substance or other item governed by the federal Controlled Substances Act (21 U.S.C. -
(12) United States Patent (10) Patent N0.: US 6,310,270 B1 Huang Et Al
US006310270B1 (12) United States Patent (10) Patent N0.: US 6,310,270 B1 Huang et al. (45) Date of Patent: Oct. 30, 2001 (54) ENDOTHELIAL NOS KNOCKOUT MICE Benrath, J. et al., “Substance P and nitric oxide mediate AND METHODS OF USE Wound healing of ultraviolet photodamaged rat skin: evi dence for an effect of nitric oxide on keratinocyte prolifera (75) Inventors: Paul L. Huang, Boston; Mark C. tion,” Nerosci. Letts. 200.'17—20 (Nov. 1995). Fishman, Newton Center; Michael A. Boeckxstaens, G.E. et al., “Evidence for nitric oxide as Moskowitz, Belmont, all of MA (US) mediator of non—adrenergic, non—cholinergic relaxations induced by ATP and GABA in the canine gut,” Br J. (73) Assignee: The General Hospital Corporation, Pharmacol. 102:434—438 (1991). Boston, MA (US) Bohme, G.A. et al., “Possible involvement of nitric oxide in ( * ) Notice: Subject to any disclaimer, the term of this long—term potentiation,” Eur J. Pharmacol. 199:379—381 patent is extended or adjusted under 35 (1991). U.S.C. 154(b) by 0 days. Booth, R.F.G. et al., “Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular (21) Appl. No.: 08/818,082 manipulation,” Atherosclerosis 76.'257—268 (1989). Bredt, D.S. et al., “Localization of nitric oxide synthase (22) Filed: Mar. 14, 1997 indicating a neural role for nitric oxide,” Nature Related US. Application Data 347:768—770. (60) Provisional application No. 60/027,362, ?led on Sep. 18, Bredt, D.S. and Snyder, S.H., “Isolation of nitric oxide 1996, and provisional application No. -
WO 2008/044045 Al
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 17 April 2008 (17.04.2008) WO 2008/044045 Al (51) International Patent Classification: MURRAY, Christopher William [GB/GB]; 436 Cam A61K 31/438 (2006.01) C07D 491/10 (2006.01) bridge Science Park, Milton Road, Cambridge CB4 OQA A61K 31/439 (2006.01) C07D 471/04 (2006.01) (GB). A61K 31/403 (2006.01) C07D 471/10 (2006.01) A61K 31/00 (2006.01) C07D 491/08 (2006.01) (74) Agent: HUTCHINS, Michael, Richard; M. R. Hutchins C07D 209/44 (2006.01) C07D 401/04 (2006.01) & Co., 23 Mount Sion, Tunbridge Wells, Kent TN 1 ITZ C07D 209/08 (2006.01) C07D 401/12 (2006.01) (GB). C07D 215/08 (2006.01) C07D 419/10 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/GB2007/003891 AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (22) International Filing Date: 12 October 2007 (12.10.2007) ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (25) Filing Language: English LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (26) Publication Language: English PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (30) Priority Data: ZM, ZW 60/829.221 12 October 2006 (12.10.2006) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): ASTEX kind of regional protection available): ARIPO (BW, GH, THERAPEUTICS LIMITED [GB/GB]; 436 Cambridge GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Science Park, Milton Road, Cambridge CB4 OQA (GB). -
Nitric Oxide Synthase Inhibitors As Antidepressants
Pharmaceuticals 2010, 3, 273-299; doi:10.3390/ph3010273 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review Nitric Oxide Synthase Inhibitors as Antidepressants Gregers Wegener 1,* and Vallo Volke 2 1 Centre for Psychiatric Research, University of Aarhus, Skovagervej 2, DK-8240 Risskov, Denmark 2 Department of Physiology, University of Tartu, Ravila 19, EE-70111 Tartu, Estonia; E-Mail: [email protected] (V.V.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +4577893524; Fax: +4577893549. Received: 10 November 2009; in revised form: 7 January 2010 / Accepted: 19 January 2010 / Published: 20 January 2010 Abstract: Affective and anxiety disorders are widely distributed disorders with severe social and economic effects. Evidence is emphatic that effective treatment helps to restore function and quality of life. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology of mood and stress-related disorders. However, a few clinical and several pre-clinical studies, strongly suggest involvement of the nitric oxide (NO) signaling pathway in these disorders. Moreover, several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO, and distinct classes of antidepressants have been found to modulate the hippocampal NO level in vivo. The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis. This paper reviews the effect of drugs modulating NO synthesis in anxiety and depression. Keywords: nitric oxide; antidepressants; psychiatry; depression; anxiety 1. Introduction Recent data from Denmark and Europe [1,2], indicate that brain disorders account for 12% of all direct costs in the Danish health system and 9% of the total drug consumption was used for treatment of brain diseases. -
7-Nitro Indazole, a Selective Neuronal Nitric Oxide Synthase Inhibitor in Vivo, Impairs Spatial Learning in The
Downloaded from learnmem.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH 7-Nitro Indazole, a Selective Neuronal Nitric Oxide Synthase Inhibitor in Vivo, Impairs Spatial Learning in the Rat Christian H61scher, 1'3 Liam McGlinchey, 1 Roger Anwyl, 2 and Michael J. Rowan ~Department of Pharmacology and Therapeutics and 2Department of Physiology Trinity College Dublin 2, Republic of Ireland Abstract Introduction Nitric oxide (NO) is an intercellular messen- Nitric oxide (NO) is an intercellular ger that plays a role in many physiological systems. messenger that has been suggested to have In the nervous system, NO acts as a neurotrans- a role in learning and memory formation. mitter (Amir 1992). The enzyme NO synthase Previous studies with nonselective NO (NOS) has been found in neurons (Bredt and Sny- synthase inhibitors have produced der 1992; Vincent and Kimura 1992), and endog- contradictory results in learning enous NO production occurs in neuronal cultures experiments. However, these drugs also (Ma et al. 1991). At least three isoforms of NOS produced blood pressure changes, as NO is have been identified. NOS isoform I is found in an endothelial-derived relaxing factor. A neurons, whereas isoform III has been purified novel NO synthase inhibitor, 7-nitro from endothelial cells (Schmidt et al. 1992). Both indazole (7-NI), as a dose (30 mg/kg i.p.) isoforms are Ca 2+ dependent (Moncada and shown previously to inhibit neuronal NO Palmer 1992). Isoform type II is inducible and synthase by 85% without affecting blood Ca 2+ independent. It is found in most tissues of pressure, produced amnesic effects both in the body (Kilbourn 1991; Nathan 1991). -
TSPO in Steroid Neuroendocrinology
231 1 V SELVARAJ and L N TU TSPO in neuroendocrinology 231:1 R1–R30 Review Current status and future perspectives: TSPO in steroid neuroendocrinology Correspondence should be addressed Vimal Selvaraj and Lan N Tu to V Selvaraj Email Department of Animal Science, Cornell University, Ithaca, New York, USA [email protected] Abstract The mitochondrial translocator protein (TSPO), previously known as the peripheral Key Words benzodiazepine receptor (PBR), has received significant attention both as a diagnostic f neurosteroid biomarker and as a therapeutic target for different neuronal disease pathologies. f steroid Recently, its functional basis believed to be mediating mitochondrial cholesterol import f brain for steroid hormone production has been refuted by studies examining both in vivo f spinal cord and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental f nervous system gap in the understanding of TSPO function in the nervous system, and its putative f mitochondria pharmacology in neurosteroid production. In this review, we discuss several recent f cholesterol Endocrinology findings in steroidogenic cells that are in direct contradiction to previous studies, and f hormone of necessitate a re-examination of the purported role for TSPO in de novo neurosteroid f inflammation biosynthesis. We critically examine the pharmacological effects of different TSPO- Journal binding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the Journal of Endocrinology true potential of this therapeutic target in medicine may be realized. -
WO 2013/092791 Al 27 June 2013 (27.06.2013) P O 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 WO 2013/092791 Al 27 June 2013 (27.06.2013) P O P C T (51) International Patent Classification: field Heath, Bishops Stortford, Hertfordshire CM22 7EG C07D 471/04 (2006.01) A61P 9/10 (2006.01) (GB). A61K 31/529 (2006.01) (74) Agent: NICHOL, Maria; Galapagos NV, Chesterford Re (21) International Application Number: search Park, Saffron Walden, Essex CB10 1XL (GB). PCT/EP2012/076275 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 20 December 2012 (20. 12.2012) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/578,979 22 December 201 1 (22. 12.201 1) US NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (71) Applicant: GALAPAGOS NV [BE/BE]; Industriepark RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, Mechelen Noord, Generaal De Wittelaan L 11/A3, B-2800 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, Mechelen (BE). -
Cgmp Signaling and Vascular Smooth Muscle Cell Plasticity
Journal of Cardiovascular Development and Disease Review cGMP Signaling and Vascular Smooth Muscle Cell Plasticity Moritz Lehners †, Hyazinth Dobrowinski †, Susanne Feil and Robert Feil * ID Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany; [email protected] (M.L.); [email protected] (H.D.); [email protected] (S.F.) * Correspondence: [email protected]; Tel.: +49-7071-2973350 † These authors contributed equally to this work. Received: 14 March 2018; Accepted: 16 April 2018; Published: 19 April 2018 Abstract: Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as atherosclerosis. Recent studies have shown that VSMCs contribute to the development of atherosclerotic plaques by clonal expansion and transdifferentiation to macrophage-like cells. VSMCs express a variety of cGMP generators and effectors, including NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), respectively. According to the traditional view, cGMP inhibits VSMC proliferation, but this concept has been challenged by recent findings supporting a stimulatory effect of the NO-cGMP-cGKI axis on VSMC growth. Here, we summarize the relevant studies with a focus on VSMC growth regulation by the NO-cGMP-cGKI pathway in cultured VSMCs and mouse models of atherosclerosis, restenosis, and angiogenesis. We discuss potential reasons for inconsistent results, such as the use of genetic versus pharmacological approaches and primary versus subcultured cells. We also explore how modern methods for cGMP imaging and cell tracking could help to improve our understanding of cGMP’s role in vascular plasticity. -
7-Nitro Inctazole, an Inhibitor of Neuronal Nitric Oxide Synthase, Attenuates Pilocarpine-Induced Seizures
CORE Metadata, citation and similar papers at core.ac.uk Provided by Erasmus University Digital Repository eJp ELSEVIER European Journal of Pharmacology287 (1995) 211-213 Short communication 7-Nitro inctazole, an inhibitor of neuronal nitric oxide synthase, attenuates pilocarpine-induced seizures Redmer Van Leeuwen, Ren6 De Vries, Mihailo R. Dzoljic * Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, Netherlands Received 26 June 1995; revised 9 October 1995; accepted 13 October 1995 Abstract 7-Nitro indazole (25-100 mg/kg i.p.), an inhibitor of neuronal nitric oxide (NO) synthase, attenuated the severity of pilocarpine (300 mg/kg i.p.)-induced seizures in mice. This indicates that the decreased neuroexcitability of the central nervous system (CNS) following administration of 7-nitro indazole may be due to inhibition of neuronal NO synthase, implying that NO acts as an excitatory and proconvulsant factor in the CNS. Keywords: Epilepsy; Nitric oxide (NO); Nitric oxide (NO) synthase; 7-Nitro indazole; Pilocarpine; Seizure 1. Introduction nine), potentiated seizures induced in rats by various convulsant compounds, such as quinolinate (Haberny As a retrograde messenger, nitric oxide (NO) in- et al., 1992), kainic acid (Rondouin et al., 1993) and duces presynaptically the release of several neurotrans- bicuculline (Wang et al., 1994). These data indicated mitters, including the excitatory amino acid, L-gluta- that NO is an endogenous anticonvulsant substance. mate (Montague et al., 1994). This indicates that NO All NO synthase inhibitors used in these studies are deranges the neurotransmitter balance in the central alkyl esters of arginine and affect both neuronal NO nervous system (CNS) and affects neuronal excitability. -
Modulation of Neurogenesis by PDE Inhibition
(19) & (11) EP 2 377 530 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 19.10.2011 Bulletin 2011/42 A61K 31/40 (2006.01) A61K 45/06 (2006.01) A61K 31/4015 (2006.01) A61K 31/403 (2006.01) (2006.01) (2006.01) (21) Application number: 10013573.0 A61K 31/416 A61K 31/4166 A61K 31/4184 (2006.01) A61K 31/505 (2006.01) (2006.01) (2006.01) (22) Date of filing: 20.10.2006 A61P 25/00 A61K 31/401 (84) Designated Contracting States: • Lorrain, Kym, I. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR San Diego HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI California 92124 (US) SK TR • Pires, Jammieson, C. Chula Vista (30) Priority: 21.10.2005 US 729366 P CA 91911 (US) 21.03.2006 US 784605 P • Treuner, Kai 17.07.2006 US 807594 P San Diego California 92122 (US) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Roques, Sarah Elizabeth 06826395.3 / 1 940 389 J.A. Kemp & Co. 14 South Square (71) Applicant: Braincells, Inc. Gray’s Inn San Diego, CA 92121 (US) London WC1R 5JJ (GB) (72) Inventors: Remarks: • Barlow, Carrolee This application was filed on 12-10-2010 as a Del Mar divisional application to the application mentioned California 92014 (US) under INID code 62. • Carter, Todd, A. San Diego California 92129 (US) (54) Modulation of neurogenesis by PDE inhibition (57) The instant disclosure describes methods for methods based on use of a PDE agent, optionally in com- treating diseases and conditions of the central and pe- bination with one or more other neurogenic agents, to ripheral nervous system by stimulating or increasing neu- stimulate or activate the formation of new nerve cells.