Effects of Γ-Aminobutyric Acid on Food Intake and Appetite in Mandarin Fish Siniperca Chuatsi

Total Page:16

File Type:pdf, Size:1020Kb

Effects of Γ-Aminobutyric Acid on Food Intake and Appetite in Mandarin Fish Siniperca Chuatsi 第 41 卷 第 6 期 水 生 生 物 学 报 Vol. 41, No. 6 2017 年 11 月 ACTA HYDROBIOLOGICA SINICA Nov., 2017 doi: 10.7541/2017.162 EFFECTS OF γ-AMINOBUTYRIC ACID ON FOOD INTAKE AND APPETITE IN MANDARIN FISH SINIPERCA CHUATSI HUANG Dong1, 2, LIANG Xu-Fang1, 2, YUAN Xiao-Chen1, 2, CAI Wen-Jing1, 2, LI Ai-Xuan1, 2, HE Shan1, 2 and XUE Min3 (1. College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan 430070, China; 2. Freshwa- ter Aquaculture, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture, Wuhan 430070, China; 3. National Aquafeed Safety Assessment Station, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China) Abstract: γ-Aminobutyric acid (GABA) has been established as an important regulator of food intake in mammals, but its role in fish remains scant. The aim of this study was to investigate the effects of GABA on food intake in mandarin fish (Siniperca chuatsi). Fish received intracerebroventricular (ICV) injection of sa- line and different doses of GABA (50, 125, 500 and 2000 μg). Food intake increased significantly in 125 μg GABA group within 2h. The RT-qPCR data demonstrated that up-regulation of NPY and AgRP, and down- regulation of CART and POMC were consistent with higher food intake of mandarin fish. The mRNA expres- sion of Leptin-R decreased significantly at all the four doses of GABA at 0.5h and 2h compared to the saline injected fish. These results indicated that GABA could affect the appetite by regulating leptin signaling path- way and thus resulting in alteration of food intake. Our findings could provide theory basis for GABA applica- tion in aquaculture feeds. Key words: γ-Aminobutyric acid; Mandarin fish; Food intake; Gene expression; Leptin signaling path- way CLC number: S965.1 Document code: A Article ID: 1000-3207(2017)06-1311-07 γ-Aminobutyric acid (GABA), a non-protein were observed following injections of the agonist or amino acid, distributes widely in nature and serves as antagonists of GABA into the hypothalamus[2, 11—15]. a major inhibitory neurotransmitter in the central Likewise, GABA is also involved in the regulation of nervous system[1, 2]. It has been implicated in several a number of physiological functions in fish. It was centrally mediated physiological functions such as found that injecting GABA intraperitoneally caused neurotransmission[3], blood pressure regulator[4], hor- an increase of serum GTH levels in regressed or early monal regulator[5], relaxation regulator[6] and sleep- maturing fish, rather in late maturing animals[16]. An lessness and depression regulator[7]. Moreover, it has ICV injection of muscimol caused an acute and dose been established as an important regulator of food in- dependent increase in locomotor activity of juvenile take in mammals[8—10]. Many previous studies were spring chinook salmon[17]. Interactions in goldfish carried out by using commercial GABA, GABA recep- were found between feeding behaviors and ORXR-β- [18] tor agonist or GABA receptor antagonist in mamma- GABAAR subunit . However, effects of GABA on lian species. It was reported that injection of GABA into food intake of teleost remain largely unknown. There- the ventromedial hypothalamus of satiated rats in- fore, further studies are needed to elucidate the poten- duced further consumption of food. Similar effects tial role of GABA on food intake of fish. Received date: 2016-11-24; Accepted date: 2017-04-27 Foundation item: Supported by the National Basic Research Program of China (2014CB138601); the Fundamental Research Funds for the Central Universities (2015PY041) Brief introduction of author: Huang Dong (1991—), Male, born in Shanxi; Master student; major in molecular nutrition of fish. E-mail: [email protected] Corresponding author: Liang Xu-Fang, E-mail: [email protected] 1312 水 生 生 物 学 报 41 卷 As is known to us, the regulation of appetite mrigola (initial body weight: 0.16±0.02 g) (Wuhan, which controls food intake is a complex phenomenon China) at 8:00 am and 17:00 pm every day. Animals involving interactions between the brain and periphe- were acclimated to these conditions for at least 2 weeks ral signals. A few peptides are now recognized to play before the experiment. an important role in the regulation of appetite, which 1.3 Drug and treatment exist in the same neuron or may have interactions The GABA was purchased from Sigma Bio- with GABA. Neuropeptide Y (NPY) neurons coex- chemicals, Dorset, UK. The drug was dissolved in pressing GABA and agouti-related protein (AgRP) teleost saline (20 mg Na2CO3 per 100 mL of 0.6% [19] stimulate appetite . In addition, NPY, AgRP, and NaCl). Doses of drug were selected based on previ- GABA released in the ARC suppress the restraint of ous studies[24—26], which were chosen for the follow- proopiomelanocortin (POMC) neurons coexpressing ing experiments. The ICV injections were carried out α-melanocyte stimulating hormone (α-MSH) and co- using a 0.5 mm Microlance needle connected to a 5 μL caine and amphetamine regulated transcript (CART) [19] Hamilton microsyringe. The needle was performed on appetite . Leptin, a product of the obese (ob) freehand through the central junction between the gene, bindings with leptin receptor (Leptin-R) and frontal and parietal bones. The procedure of ICV in- acts directly on the hypothalamus to inhibit nore- jection and accuracy of injection placement into the pinephrine efflux (NE) efflux through GABA[20]. Al- ventricular regions of the fish brain followed the though information about the feeding regulation [27] method of De Pedro et al . After injection, the mechanism of these peptides is increasing, the intera- wounds were covered immediately with vaseline. ctions of GABA with them on food intake of fish are 1.4 Effects of ICV administration of GABA on food still limited. intake Mandarin fish (Siniperca chuatsi), a demersal After the acclimation period, 30 food-deprived piscivore, is one of the most valuable food fish native (24h) fish were anesthetized with MS-222 (1鲶10000) to the freshwaters of China. It is one of the chief eco- and weighted when they lost equilibrium, which were nomic edible fish in China and in other countries due [21, 22] divided into five groups that received ICV injection, to its large size, fast growth and delicious flesh . respectively. GABA at 50 μg, 125 μg, 500 μg and In addition, it has distinct food preference. In the 2000 μg, and one control group, which received ICV wild, it feed solely on live fry of other fish species once the fry start feeding[23]. injection of the same volume of teleost saline (5 μL). In the present study, we investigated food intake The fish were habituated in anaesthetic-free water and mRNA expression profiles of five representative within 1—2min to help them recovered equilibrium appetite-related genes in the brain of mandarin fish and normal swimming activity after injection. Every after GABA administration. This study will provide a mandarin fish was then transferred to a aquaria which better understanding of GABA in mediating food in- contained enough pre-weighted prey fish (average take of fish. body weight: 0.16 g) immediately. The food intake was measured by directly observing and recording the 1 Materials and methods number of prey fish eaten by individual mandarin fish 1.1 Ethics statement after 0.5h, 2h and 4h. The formula is as follows: This study was carried out in strict accordance FI=Wi–(Wf×F) where Wi=initial food weight, Wf=re- with the recommendations in the Guide for the Care maining food weight and F=correction factor[27]. and Use of Laboratory Animals of the National Vete- 1.5 Effects of ICV administration of GABA on gene rinary and Quarantine Service. The protocol was ap- expression proved by the Committee on the Ethics of Animal Ex- In order to examine effects of GABA on brain periments of the Huazhong Agricultural University. NPY, AgRP, CART, POMC and Leptin-R mRNA ex- 1.2 Animals pressions, another experiment was performed using The mandarin fish were obtained from Wuhan the uninjectd stock of mandarin fish, which received Freshwater Fish Farm (Wuhan, China). Prior to the the same treatment without giving prey fish. Fish initiation of the experiment, 100 mandarin fish were were then sampled at 0.5h and 2h after injection carried out in 2 cylindrical plastic tanks (350 L) and without feeding. Brains of both groups were dissec- were kept under controlled light-dark conditions (12 ted and immediately snap-frozen in liquid nitrogen Light /12 Dark) with a constant flow of filtered water and stored at –80℃ for RNA isolation and sub- and the water temperature was regulated to 23—25℃. sequent analyses. The fish were fed with (2% of bodyweight) Cirrhina Total RNA was extracted using Trizol reagent 6 期 黄 东等: γ-氨基丁酸对鳜摄食和食欲的影响 1313 (TaKaRa, Japan), treated with RQI RNase-Free DNase value method[29]. All amplifications were performed (TaKaRa, Japan) to remove DNA contaminant, and in triplicate for each RNA sample. then spectrophotometrically quantified. For each re- 1.6 Statistical analyses verse transcription reaction, RNA was subjected to All data were presented as mean±SEM (standard cDNA synthesis by SuperScriptTM II RT reverse tran- error of the mean). Statistical analysis was performed scriptase (TaKaRa, Japan) according to reagent’s in- by a one-way analysis of variance (one-way AN- structions. The selected gene coding sequence were OVA) using SPSS 19.0 with Duncan’s multiple com- based on the results of transcriptome sequencing of parisons test. Statistical significance was determined mandarin fish which were mapped to the mandarin at the 5% level. fish genome by the Short Oligonucleotide Analysis 2 Results [28] Package SOAP aligner/soap2 .
Recommended publications
  • Thesis Rests with Its Author
    University of Bath PHD A modelling study of the ligand-gated ion-channel superfamily of receptors Cockcroft, Victor Barrie Award date: 1992 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 08. Oct. 2021 A MODELLING STUDY OF THE LIGAND-GATED ION-CHANNEL SUPERFAMILY OF RECEPTORS. submitted by Victor Barrie Cockcroft for the degree of Ph.D. at the University of Bath 1992 Copyright Attention is drawn to the fact that the copyright of this thesis rests with its author. This copy of the thesis has been supplied on the condition that anyone who con­ sults it is understood to recognize that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published with­ out the prior written consent of the author.
    [Show full text]
  • Assessment of Molecular Action of Direct Gating and Allosteric Modulatory Effects of Carisoprodol (Somartm) on GABA a Receptors
    Graduate Theses, Dissertations, and Problem Reports 2015 Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors Manoj Kumar Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Kumar, Manoj, "Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors" (2015). Graduate Theses, Dissertations, and Problem Reports. 6022. https://researchrepository.wvu.edu/etd/6022 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. ASSESSMENT OF MOLECULAR ACTION OF DIRECT GATING AND ALLOSTERIC MODULATORY EFFECTS OF MEPROBAMATE (MILTOWN®) ON GABAA RECEPTORS Manish Kumar, MD, MS Dissertation submitted to the School of Pharmacy at West Virginia University in partial fulfillment of Requirements
    [Show full text]
  • Benzodiazepines and the GABA, Receptor: Effecs of C~~UB~Cexposure
    The University of Alberta Benzodiazepines and the GABA, Receptor: Effecs of C~~UB~CExposure Michelle Ingird Arnot O A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillrnent of the requirements for the degree of Doctor of Philosophy. Department of Pharmacology Edmonton, Alberta FaIl, 1998 National Library Bibliothèque nationale of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395, me Wellington OüawaON K1AW ûüawaON K1AON4 Canada canada The author has granted a non- L'auteur a accorde une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distn'buer ou copies of this thesis in microform, vendre des copies de cette thése sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur format élecîronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thése ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. A mind once stretched by a new idea, never regains its original dimensions. - Author Unknown ABSTRACT The benzodiazepine pharmacological profile includes sedation. anxiolysis. muscle relaxation and anticonvulsant effects; however. after long term treatment with full agonists tolerancc develops to certain aspects of this profile. These cornpounds produce their overt effects via allosrenc modulation of the GABA, receptor.
    [Show full text]
  • World of Cognitive Enhancers
    ORIGINAL RESEARCH published: 11 September 2020 doi: 10.3389/fpsyt.2020.546796 The Psychonauts’ World of Cognitive Enhancers Flavia Napoletano 1,2, Fabrizio Schifano 2*, John Martin Corkery 2, Amira Guirguis 2,3, Davide Arillotta 2,4, Caroline Zangani 2,5 and Alessandro Vento 6,7,8 1 Department of Mental Health, Homerton University Hospital, East London Foundation Trust, London, United Kingdom, 2 Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom, 3 Swansea University Medical School, Institute of Life Sciences 2, Swansea University, Swansea, United Kingdom, 4 Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy, 5 Department of Health Sciences, University of Milan, Milan, Italy, 6 Department of Mental Health, Addictions’ Observatory (ODDPSS), Rome, Italy, 7 Department of Mental Health, Guglielmo Marconi” University, Rome, Italy, 8 Department of Mental Health, ASL Roma 2, Rome, Italy Background: There is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. While treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal, and ethical issues. Moreover, it has become very challenging for clinicians to Edited by: keep up-to-date with CEs currently available as comprehensive official lists do not exist. Simona Pichini, Methods: Using a web crawler (NPSfinder®), the present study aimed at assessing National Institute of Health (ISS), Italy Reviewed by: psychonaut fora/platforms to better understand the online situation regarding CEs.
    [Show full text]
  • Allosteric Activation Mechanism of the A1b2 2 -Aminobutyric Acid Type A
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 2542 Biophysical Journal Volume 77 November 1999 2542–2551 Allosteric Activation Mechanism of the ␣1␤2␥2 ␥-Aminobutyric Acid Type A Receptor Revealed by Mutation of the Conserved M2 Leucine Yongchang Chang and David S. Weiss Departments of Neurobiology and Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294-0021 USA ABSTRACT A conserved leucine residue in the midpoint of the second transmembrane domain (M2) of the ligand-activated ion channel family has been proposed to play an important role in receptor activation. In this study, we assessed the importance of this leucine in the activation of rat ␣1␤2␥2 GABA receptors expressed in Xenopus laevis oocytes by site-directed mutagenesis and two-electrode voltage clamp. The hydrophobic conserved M2 leucines in ␣1(L263), ␤2(L259), and ␥2(L274) subunits were mutated to the hydrophilic amino acid residue serine and coexpressed in all possible combina- tions with their wild-type and/or mutant counterparts. The mutation in any one subunit decreased the EC50 and created spontaneous openings that were blocked by picrotoxin and, surprisingly, by the competitive antagonist bicuculline. The magnitudes of the shifts in GABA EC50 and picrotoxin IC50 as well as the degree of spontaneous openings were all correlated with the number of subunits carrying the leucine mutation. Simultaneous mutation of the GABA binding site (␤2Y157S; ␤ increased the EC50) and the conserved M2 leucine ( 2L259S; decreased the EC50) produced receptors with the predicted intermediate agonist sensitivity, indicating the two mutations affect binding and gating independently.
    [Show full text]
  • Sternum. ^Sympathetic Chain \ to Prevertebral
    Durham E-Theses An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor Patten, Debra How to cite: Patten, Debra (1999) An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/4561/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 An electrophysiological study of the interaction between Fenamate NSAIDs and the GABAA receptor. Debra Patten Submitted for the Degree of Ph.D. The copyright of this thesis rests with the author. No quotation from it should be published without the written consent of the author and information derived from it should be acknowledged. 1 9 JUL 2000 Dept. of Biological Sciences University of Durham March 1999 March 1999 Table of Contents AN ELECTROPHYSIOLOGICAL STUDY OF THE INTERACTION BETWEEN FENAMATE NSAIDs AND THE GABAA RECEPTOR CHAPTER ONE: GENERAL INTRODUCTION 1.1.
    [Show full text]
  • Áiáëiîòåêà Ñòóäåíòà-Ìåäèêà Medical Student's Library
    Áiáëiîòåêà ñòóäåíòà-ìåäèêà Medical Student’s Library GENERAL PHARMACOLOGY GENERAL PHARMACOLOGY ОДЕСЬКИЙ МЕДУНІВЕРСИТЕТ Medical Student’s Library Initiated in 1999 to mark the Centenary of the Odessa State Medical University (1900 — 2000) Edited and Published by V. M. ZAPOROZHAN, the State Prize-Winner of Ukraine, Academician of the Academy of Medical Sciences of Ukraine CHIEF EDITORIAL BOARD V. M. ZAPOROZHAN, (Chief Editor), Yu. I. BAZHORA, I. S. VITENKO, V. Y. KRESYUN (Vice Chief Editor), O. O. MARDASHKO, V. K. NAPKHANYUK, G. I. KHANDRIKOVA(Senior Secretary), P. M. TCHUYEV The Odessa State Medical University Dear Reader, When in 1999 the lecturers and researchers of the Odessa State Medi- cal University started issuing a series of books united by the collection en- titled “Medical Student’s Library” they had several aims before them. Firstly, they wanted to add new books to the Ukrainian library of med- ical literature that would be written in Ukrainian, the native language of the country. These books should contain both classical information on med- icine and the latest information on the state of the art, as well as reflect extensive experience of our best professionals. Secondly, our lecturers and specialists wanted to write such books which reflected the newest subjects and courses that have recently been introduced into the curricula, and in general there have been no textbooks on these subjects and courses at that time. These two aims have successfully been coped with. Some dozens of text- books and workbooks published in these years have become a good con- tribution of their authors and publishers to the development and making of the Ukrainian national educational literature.
    [Show full text]
  • Hepatic Encephalopathy: Clinical and Experimental Studies
    HEPATIC ENCEPHALOPATHY: CLINICAL AND EXPERIMENTAL STUDIES HEPATISCHE ENCEPHALOPATHIE: KLINISCHE EN DIEREXPERIMENTELE STUDIES HEPATIC ENCEPHALOPATHY: CLINICAL AND EXPERIMENTAL STUDIES HEPATISCHE ENCEPHALOPATHIE: KLINISCHE EN DIEREXPERIMENTELE STUDIES Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam, op gezag van de rector magnificus Prof. Dr. C.J. Rijnvos en volgens het besluit van het college van Dekanen. De openbare verdediging zal plaatsvinden op woensdag 6 november 1991 om 13.45 uur door Carolina Cornelia Dimphna van der Rijt geboren te Roosendaal en Nispen ~·· !991 Offsetdrukkerij Haveka B.V .. Alblasserdam PROMOTIECOMMISSIE Promotor: Prof. Or. S.W. Schalm Overige leden: Prof. J.H.P. Wilson Prof. Dr. M. de V!ieger Prof. Dr. O.T. Terpstra voor mijn ouders CONTENTS Chapter 1. Introduction 9 Clinical aspects 9 Genera! considerations of the pathogenesis 13 Pathogenesis and implications for therapy 15 Aims of the study 22 Chapter 2. Objective measurement of hepatic encephalopathy by means of automated EEG analysis 31 Chapter 3. Quantitative EEG analysis and survival in liver disease 43 Chapter 4. Quantitative EEG analysis and evoked potentials to measure hepatic encephalopathy 51 Chapter 5. Flumazeni! does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit 57 Chapter 6. Flumazenil therapy for hepatic encephalopathy: a double-blind cross-over study 73 Chapter 7. Pharmacokinetics of flumazenil in liver disease 93 Chapter 8. Factors correlated with encephalopathy in liver disease: a logistic regression analysis 101 Chapter 9. Overt hepatic encephalopathy precipitated by zinc deficiency. A case report 121 Chapter 10. Discussion and conclusions 133 Chapter 11. Summary 141 Samenvatting 146 Dankwoord 151 Curriculum vitae 153 9 Chapter 1 INTRODUCTION 10 The pathogenesis of hepatic encephalopathy is still not known.
    [Show full text]
  • ABSTRACT Gamma Hydroxybutyrate (GHB): Mechanisms of Central
    ABSTRACT Gamma Hydroxybutyrate (GHB): Mechanisms of Central Nervous System Toxicity Eric E. Lyng Mentor: Teodoro G. Bottiglieri, Ph.D. Gamma Hydroxybutyrate (GHB) is an endogenous metabolite of gamma- aminobutyric acid (GABA) and a putative neurotransmitter found in mammalian brain. The illicit use of GHB is a growing health care concern in the U.S. Low doses have euphoric and stimulatory effects while high doses act as a CNS depressant and can cause respiratory failure. In addition to fatalities and drug facilitated rape, in 2004 over 7000 GHB overdoses were reported in the U.S. Gamma Butyrolactone (GBL) and 1,4- Butanediol (1,4-BD), precursors of GHB, can cause similar effects after being converted to GHB in the body. While GHB is a Schedule I compound, recently it was given a Schedule III classification as a drug for treatment of cataplexy associated with narcolepsy. Individuals affected by the inherited disorder succinic semialdehyde dehydrogenase (SSADH) deficiency have significant elevation of GABA and GHB in body tissues, and a range of neurological complications. Currently there is no treatment option for a GHB overdose situation or for SSADH patients. GHB has been shown to inhibit striatal dopamine release leading to sedation and loss of locomotor activity in rodents. However, GHB’s mechanism of action is poorly understood. This dissertation investigated acute and chronic effects of GBL, a precursor to GHB, on locomotor function and monoamine neurotransmitter metabolism in mice. Dose response studies were performed to characterize the effects of GBL. Compounds aimed at increasing central dopaminergic activity or antagonism of GABAergic activity were tested for their ability to antagonize the locomotor effects induced by GBL.
    [Show full text]
  • A Molecular Characterization of Agonists That Bind to Hco-UNC-49, a GABA
    A Molecular Characterization of Agonists That Bind to Hco-UNC-49, a GABA- gated Chloride Channel From Haemonchus contortus By Mark D. Kaji A Thesis Submitted in Partial Fulfillment Of the Requirements for the Degree of Masters of Science In The Faculty of Science Applied Bioscience University of Ontario Institute of Technology November, 2012 © Mark D. Kaji, 2012 Certification of Approval i Copyright Agreement ii Abstract Haemonchus contortus is a blood feeding parasitic nematode infecting ruminants causing anemia and poor health at great economic cost. The ability to pharmaceutically control infection has been challenged by the rapid development and spread of drug resistance. The discovery of new targets is therefore required for sustainable parasite control. UNC- 49 is a nematode ligand-gated ion channel that plays an important role in muscle contraction required for normal locomotion. However, little is known regarding its sensitivity to different agonists and how they interact with the binding site. This thesis describes an investigation into the efficacy of a range of classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus oocytes. The results of our electrophysiological recordings indicate that there is a size requirement for full agonism of the Hco-UNC-49 binding site. Furthermore, a number of molecules that are known to act on vertebrate GABA receptors have no effect on Hco-UNC-49. This suggests that the binding site of nematode GABA receptors does exhibit some unique properties. These findings could possibly be exploited to develop new drugs that specifically target GABA receptors from parasitic nematodes. Keywords Haemonchus contortus, GABAA agonists, GABAA receptors, homology modeling, cys- loop receptors iii Acknowledgements I would like to thank my fellow graduate students for bearing with my insanity during those marathon sessions of electrophysiology.
    [Show full text]
  • Evidence for the Involvement of the GABA-Ergic Pathway in The
    Journal of Pre-Clinical and Clinical Research 2019, Vol 13, No 3, 99-105 ORIGINAL ARTICLE www.jpccr.eu Evidence for the involvement of the GABA-ergic pathway in the anticonvulsant and antinociception activity of Propoxazepam in mice and rats Mykola Golovenko1, Anatoliy Reder1, Sergey Andronati1, Vitalii Larionov1 1 Bogatsky Physical-chemical Institute of NAS, Odessa, Ukraine Golovenko M, Reder A, Andronati S, Larionov V. Evidence for the involvement of the GABA-ergic pathway in the anticonvulsant and antinociception activity of Propoxazepam in mice and rats. J Pre-Clin Clin Res. 2019; 13(3): 99–105. doi: 10.26444/jpccr/110430 Abstract Introduction. Propoxazepam (3-alcoxyderivative of 1.4-benzodiazepine), in the tail-flick test and picrotoxin-induced convulsions showed significant analgesic and antiepileptic activity. Flumazenil (GABA antagonist) reduced its analgesic action, although antiseizure activity was changed slightly. As specific propoxazepam actions are anticonvulsant (1 subtype GABAA-R) and analgesic (2 subtype GABAA-R in the spinal cord), it can be suggested that the substance has no abuse-related side-effects. Materials and method. The possible involvement of the GABA system in the antinociceptive effect of propoxazepam was examined by administering flumazenil (1 and 10 mg/kg, i.p.), a selective GABA- receptor antagonist, 30 min prior to propoxazepam (1.8 and 10 mg/kg, orally) in rats. Picrotoxin solution (6.5 mg/kg, 95 % of lethality effect in mice) was injected subcutaneously 30 min after propoxazepam administration. Flumazenil was administered intraperitoneally 0.5 hour prior to propoxazepam administration. Time counting was starting from the convulsant injection and during the supervision time, the number of myoclonic convulsions and tonic extensia, time of their onset, as well as time to lethal effect (survival time), were registered.
    [Show full text]
  • How Adaptation of the Brain to Alcohol Leads to Dependence
    How Adaptation of the Brain to Alcohol Leads to Dependence A Pharmacological Perspective Peter Clapp, Ph.D; Sanjiv V. Bhave, Ph.D; and Paula L. Hoffman, Ph.D The development of alcohol dependence is posited to involve numerous changes in brain chemistry (i.e., neurotransmission) that lead to physiological signs of withdrawal upon abstinence from alcohol as well as promote vulnerability to relapse in dependent people. These neuroadaptive changes often occur in those brain neurotransmission systems that are most sensitive to the acute, initial effects of alcohol and/or contribute to a person’s initial alcohol consumption. Studies of these neuroadaptive changes have been aided by the development of animal models of alcohol dependence, withdrawal, and relapse behavior. These animal models, as well as findings obtained in humans, have shed light on the effects that acute and chronic alcohol exposure have on signaling systems involving the neurotransmitters glutamate, ­aminobutyric acid (GABA), dopamine, and serotonin, as well as on other signaling γ molecules, including endogenous opioids and corticotrophin­releasing factor (CRF). Adaptation to chronic alcohol exposure by these systems has been associated with behavioral effects, such as changes in reinforcement, enhanced anxiety, and increased sensitivity to stress, all of which may contribute to relapse to drinking in abstinent alcoholics. Moreover, some of these systems are targets of currently available therapeutic agents for alcohol dependence. KEY WORDS: Alcohol dependence; alcohol and other drug (AOD) dependence (AODD); addiction; neurobiology; neuroplasticity; neuroadaptation; brain; craving; withdrawal; relapse; neurotransmission; neurotransmitters; glutamate; glutamate receptors; glutamate systems; –aminobutyric acid (GABA); GABA systems; dopamine; serotonin; signaling molecules; endogenous opioids; γ opioid systems; corticotrophin­releasing factor (CRF); animal models; human studies he development of dependence consumption—and that chronic expo­ neurons.
    [Show full text]