DOCSLIB.ORG

Toxicology Mechanisms Underlying the Neurotoxicity Induced by Glyphosate-Based Herbicide in Immature Rat Hippocampus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Toxicology Mechanisms Underlying the Neurotoxicity Induced by Glyphosate-Based Herbicide in Immature Rat Hippocampus Toxicology 320 (2014) 34–45 Contents lists available at ScienceDirect Toxicology j ournal homepage: www.elsevier.com/locate/toxicol Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity Daiane Cattani, Vera Lúcia de Liz Oliveira Cavalli, Carla Elise Heinz Rieg, Juliana Tonietto Domingues, Tharine Dal-Cim, Carla Inês Tasca, ∗ Fátima Regina Mena Barreto Silva, Ariane Zamoner Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil a r a t i b s c l t r e a i n f o c t Article history: Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neu- Received 23 August 2013 rotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. Received in revised form 12 February 2014 ® The aim of this study was to investigate whether Roundup (a glyphosate-based herbicide) leads to Accepted 6 March 2014 neurotoxicity in hippocampus of immature rats following acute (30 min) and chronic (pregnancy and Available online 15 March 2014 lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally ® with 1% Roundup (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal Keywords: ® slices from 15 day old rats were acutely exposed to Roundup (0.00005–0.1%) during 30 min and experi- Glyphosate 45 2+ Calcium ments were carried out to determine whether glyphosate affects Ca influx and cell viability. Moreover, 14 we investigated the pesticide effects on oxidative stress parameters, C-␣-methyl-amino-isobutyric acid Glutamatergic excitotoxicity 14 Oxidative stress ( C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that ® 45 2+ Kinase pathways acute exposure to Roundup (30 min) increases Ca influx by activating NMDA receptors and voltage- 2+ dependent Ca channels, leading to oxidative stress and neural cell death. The mechanisms underlying ® Roundup -induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute expo- ® 3 sure to Roundup increased H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed ® 3 that both acute and chronic exposure to Roundup decreased H-glutamate uptake and metabolism, 45 2+ 14 while induced Ca uptake and C-MeAIB accumulation in immature rat hippocampus. Taken together, ® these results demonstrated that Roundup might lead to excessive extracellular glutamate levels and consequently to glutamate excitotoxicity and oxidative stress in rat hippocampus. © 2014 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Agricultural Defense Products (Sindicato Nacional da Indústria de Produtos para Defesa Agrícola – SINDAG), in 2008 Brazil became the The annual consumption of pesticides in Brazil has increased largest consumer of pesticides in the world. The increase in pesti- alarmingly in recent years. The justification for the use of these sub- cide consumption leads to high rates of intoxication among farmers. stances is based on the improvement of agricultural productivity, Moreover, it has been suggested important associations between which places the country as one of the world’s largest produc- the bulk sale of pesticides and the increased rates of several types of ers of food. However, the risks to the environment and health are cancer, endocrine disorders and a high prevalence of neurodegen- neglected. According to the Brazilian National Trade Union for the erative diseases in agricultural workers (Londres, 2011), reinforcing the need for mechanistic investigations. Glyphosate-based herbicides lead the pesticide world market. Moreover, glyphosate is the primary active ingredient present ∗ Corresponding author at: Departamento de Bioquímica, Centro de Ciências ® in Roundup (Monsanto Company, St. Louis, MO). It has been Biológicas, UFSC, Campus Universitário, Bairro Trindade, CEP: 88040-970, Flori- ® suggested that the toxicity of Roundup is probably due to syner- anópolis, Santa Catarina, Brazil. Tel.: +55 48 3721 4747; fax: +55 48 3721 9672. gistic effects between glyphosate and other formulation products E-mail addresses: [email protected], [email protected], [email protected] (A. Zamoner). (Marc et al., 2002; El-Shenawy, 2009), such as the surfactant http://dx.doi.org/10.1016/j.tox.2014.03.001 0300-483X/© 2014 Elsevier Ireland Ltd. All rights reserved. D. Cattani et al. / Toxicology 320 (2014) 34–45 35 polyethoxylated tallowamine (POEA) which might facilitate neurotransmitters metabolism, and poor radical scavenging mech- glyphosate penetration through plasma membranes potentiating anisms (Chong et al., 2005). its toxicity (Williams et al., 2000; Tsui and Chu, 2003; Richard et al., Taking into account the previous studies demonstrating that 2005; Benachour and Séralini, 2009). exposure to glyphosate might be associated with neurotoxicity and The planting of transgenic soybeans resistant to glyphosate- oxidative damage, the aim of this study was to determine whether ® ® Roundup (Glyphosate resistant soybeans, GRS) has greatly Roundup leads to neurotoxicity in hippocampus of immature enhanced the consumption of this herbicide in Brazilian crops. rats following acute (30 min) and chronic (pregnancy and lacta- In this context, it was recently reported a teratogenic action of tion) pesticide exposure. Then, we investigated the involvement 2+ herbicides based on glyphosate to vertebrates (Paganelli et al., of Ca , intracellular signaling pathways and oxidative damage on ® 2010), warning of the need to evaluate the use of the product the mechanisms underlying Roundup -induced neurotoxicity in in agriculture. Moreover, Benachour and Séralini (2009) recently rat hippocampus. Moreover, this study investigated whether acute demonstrated that glyphosate formulations induce apoptosis and or maternal exposure to a glyphosate-based herbicide alters glu- necrosis in human umbilical, embryonic, and placental cells. This tamatergic system by interfering in the neurotransmitter uptake, herbicide was also associated with induction of oxidative stress release and/or metabolism within the hippocampal cells. and neuroinflamation (El-Shenawy, 2009; Astiz et al., 2012). More- over, glyphosate was able to provoke oxidative stress in specific 2. Material and methods brain regions: substantia nigra, cerebral cortex and hippocampus. However, most of these studies were carried out by using the com- 2.1. Radiochemical and compounds mercial formulations, and not pure glyphosate, suggesting that 3 3 further studies are necessary to examine whether the pesticide L-[2,3- H] glutamic acid ([ H] glutamate) (specific activity formulation may lead to neurotoxicity. 49 Ci/mmol) was purchased from Amersham (Oakville, Ontario, 45 2+ It has been suggested that pesticide exposure could be a risk Canada). CaCl2 (specific activity of 321 kBq/mg of Ca ) and factor for neurodegenerative disorders (Le Couteur et al., 1999; Optiphase Hisafe III biodegradable liquid scintillation were 14 Kirby et al., 2001; Barlow et al., 2005; Patel et al., 2006). In this purchased from PerkinElmer (Waltham, MA). ␣-[ C] methy- 14 context, occupational pesticide exposure leads to oxidative dam- laminoisobutyric acid ([ C] MeAIB) (sp.act. 1.85 GBq/mmol) was age, increases the risk of incidence of Parkinson’s and Alzheimer’s purchased from Du Pont, NEN Products, MA, USA. The herbicide ® disease, and also might accelerate age-related neurodegeneration Roundup Original (Homologation number 00898793) containing (Wang et al., 2006; Peng et al., 2007; Hayden et al., 2010); how- glyphosate 360 g/L is a commercial formulation registered in the ever, it is unclear as to which pesticides and what mechanisms Brazilian Ministry of Agriculture, Livestock and Supply (Ministério of action may contribute to the neurodegenerative condition. In da Agricultura, Pecuária e Abastecimento – MAPA). Nifedipine, this context, it has been reported that acute and chronic expo- N-[2-(p-Bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide sure to glyphosate might cause parkinsonism, a condition similar (H89), (Bisindoylmaleimidine IX, 2-{1-[3-(Amidinothio)propyl]- } to Parkinson’s disease (Barbosa et al., 2001; Wang et al., 2011). 1H-indol-3-yl -3-(1-methylindol-3-yl)maleimide ethanesulfonate Barbosa and colleagues (2001) reported a case of a 54-year-old salt) Ro 31-8220, d(–)-2-amino-5-phosphonopentanoic acid (AP5), man who accidentally sprayed himself with the chemical agent KN-93, (+)-␣-methyl-4-carboxyphenylglycine (MCPG) and flunar- glyphosate and one month later he developed parkinsonism. One izine were purchased from Sigma Chemical Company (St. Louis, year later, the patient presented a slow resting tremor in the left MO, USA). The G6PD assay kit was kindly provided by INTERCIEN- hand and arm, accompanied by impairment of short-term mem- TÍFICA (São José dos Campos, SP, Brazil). All other chemicals were ory. Further, Wang et al. (2011) reported a case of parkinsonism of analytical grade. following chronic exposure to glyphosate in a previously healthy 44-year-old woman who worked for 3 years in a chemical factory, 2.2. Animals exclusively in the glyphosate production division. The glyphosate neurotoxicity was associated with rigidity, slowness and resting Wistar rats were bred in animal house and maintained
Load more

Recommended publications
  • Crews Lab Discovers Inflammatory Mechanisms Underlying Alcohol
    research alcohol actions on brain, liver, pancreas, fetus, the The Director’s Column endocrine system and the immune system, has contributed Thanks for your gifts to our Center! to Crews’ insights. Alternatively, I suspect that he A. Leslie Morrow, Ph.D. assembled this diverse group of researchers to study alcohol Dean’’’ s Club Ms. Carolyn S. Corn Mr. and Mrs. Ben Madore Associate Director, actions across so many systems of the body for the very Ms. Harriet W. Crisp Bowles Center for (annual gifts of $5000 and above) Ms. Regina J. Mahon purpose of discovering how the complex systemic and Mr. and Mrs. Ray Damerell Alcohol Studies Dr. William Maixner molecular roles of alcohol go awry in the disease of Center Line James A. Bowles Mr. Lewis A. Dancy Mrs. Melissa M. Mann Bowles Center for Alcohol Studies alcoholism. Mr. John N. Howard, Jr. Mr. F. E. Danielus Mr. and Mrs. H. J. McCarthy School of Medicine, University of North Carolina at Chapel Hill Mr. and Mrs. Robert F. Schaecher Mr. Stephen M. Dean and Ms. Patricia L. Ms. Michelle McCarthy This integration of research across systems, organs, brain Ms. Ann Lewallen Spencer Amend Mr. and Mrs. Robert H. McConville, Jr. Dr. Fulton Crews’ brilliance can be attributed in part to regions, human development and the progression to Our mission is to conduct, coordinate, and promote basic and clinical research on the causes, prevention, and treatment of alcoholism and alcoholic disease. Tennessee Medical Foundation Ms. Elizabeth L. Deaver Mr. and Mrs. Loyce L. McCormick his understanding that human beings are not just a alcoholism is the hallmark of research in the Bowles Center Ms.
    [Show full text]
  • Assessing Neurotoxicity of Drugs of Abuse
    National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Assessing Neurotoxicity of Drugs of Abuse 136 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Assessing Neurotoxicity of Drugs of Abuse Editor: Lynda Erinoff, Ph.D. NIDA Research Monograph 136 1993 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT This monograph is based on the papers and discussions from a technical review on “Assessing Neurotoxicity of Drugs of Abuse” held on May 20-21, 1991, in Bethesda, MD. The technical review was sponsored by the National Institute on Drug Abuse (NIDA). COPYRIGHT STATUS NIDA has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company.
    [Show full text]
  • The Cross-Talk of HIV-1 Tat and Methamphetamine in HIV-Associated Neurocognitive Disorders
    REVIEW published: 23 October 2015 doi: 10.3389/fmicb.2015.01164 The cross-talk of HIV-1 Tat and methamphetamine in HIV-associated neurocognitive disorders Sonia Mediouni 1, Maria Cecilia Garibaldi Marcondes 2, Courtney Miller 3,4, Jay P. McLaughlin 5 and Susana T. Valente 1* 1 Department of Infectious Diseases, The Scripps Research Institute, Jupiter, FL, USA, 2 Department of Molecular and Cellular Neurosciences, The Scripps Research Institute, La Jolla, CA, USA, 3 Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA, 4 Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA, 5 Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA Antiretroviral therapy has dramatically improved the lives of human immunodeficiency virus 1 (HIV-1) infected individuals. Nonetheless, HIV-associated neurocognitive disorders (HAND), which range from undetectable neurocognitive impairments to severe dementia, still affect approximately 50% of the infected population, hampering their quality of life. The persistence of HAND is promoted by several factors, including longer life expectancies, Edited by: the residual levels of virus in the central nervous system (CNS) and the continued Venkata S. R. Atluri, presence of HIV-1 regulatory proteins such as the transactivator of transcription (Tat) Florida International University, USA Reviewed by: in the brain. Tat is a secreted viral protein that crosses the blood–brain barrier into the Masanori Baba, CNS, where it has the ability to directly act on neurons and non-neuronal cells alike. Kagoshima University, Japan These actions result in the release of soluble factors involved in inflammation, oxidative Shilpa J. Buch, University of Nebraska Medical stress and excitotoxicity, ultimately resulting in neuronal damage.
    [Show full text]
  • The Role of Excitotoxicity in the Pathogenesis of Amyotrophic Lateral Sclerosis ⁎ L
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1762 (2006) 1068–1082 www.elsevier.com/locate/bbadis Review The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis ⁎ L. Van Den Bosch , P. Van Damme, E. Bogaert, W. Robberecht Neurobiology, Campus Gasthuisberg O&N2, PB1022, Herestraat 49, B-3000 Leuven, Belgium Received 21 February 2006; received in revised form 4 May 2006; accepted 10 May 2006 Available online 17 May 2006 Abstract Unfortunately and despite all efforts, amyotrophic lateral sclerosis (ALS) remains an incurable neurodegenerative disorder characterized by the progressive and selective death of motor neurons. The cause of this process is mostly unknown, but evidence is available that excitotoxicity plays an important role. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS. The most important one is that the only drug proven to slow the disease process in humans, riluzole, has anti-excitotoxic properties. Moreover, consumption of excitotoxins can give rise to selective motor neuron death, indicating that motor neurons are extremely sensitive to excessive stimulation of glutamate receptors. We will summarize the intrinsic properties of motor neurons that could render these cells particularly sensitive to excitotoxicity. Most of these characteristics relate to the way motor neurons handle Ca2+, as they combine two exceptional characteristics: a low Ca2+-buffering capacity and a high number of Ca2+-permeable AMPA receptors. These properties most likely are essential to perform their normal function, but under pathological conditions they could become responsible for the selective death of motor neurons.
    [Show full text]
  • The Neurotoxin Β-N-Methylamino-L-Alanine (BMAA)
    The neurotoxin β-N-methylamino-L-alanine (BMAA) Sources, bioaccumulation and extraction procedures Sandra Ferreira Lage ©Sandra Ferreira Lage, Stockholm University 2016 Cover image: Cyanobacteria, diatoms and dinoflagellates microscopic pictures taken by Sandra Ferreira Lage ISBN 978-91-7649-455-4 Printed in Sweden by Holmbergs, Malmö 2016 Distributor: Department of Ecology, Environment and Plant Sciences, Stockholm University “Sinto mais longe o passado, sinto a saudade mais perto.” Fernando Pessoa, 1914. Abstract β-methylamino-L-alanine (BMAA) is a neurotoxin linked to neurodegeneration, which is manifested in the devastating human diseases amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s disease. This neurotoxin is known to be produced by almost all tested species within the cyanobacterial phylum including free living as well as the symbiotic strains. The global distribution of the BMAA producers ranges from a terrestrial ecosystem on the Island of Guam in the Pacific Ocean to an aquatic ecosystem in Northern Europe, the Baltic Sea, where annually massive surface blooms occur. BMAA had been shown to accumulate in the Baltic Sea food web, with highest levels in the bottom dwelling fish-species as well as in mollusks. One of the aims of this thesis was to test the bottom-dwelling bioaccumulation hy- pothesis by using a larger number of samples allowing a statistical evaluation. Hence, a large set of fish individuals from the lake Finjasjön, were caught and the BMAA concentrations in different tissues were related to the season of catching, fish gender, total weight and species. The results reveal that fish total weight and fish species were positively correlated with BMAA concentration in the fish brain.
    [Show full text]
  • Co-Occurrence of the Cyanotoxins BMAA, DABA and Anatoxin-A in Nebraska Reservoirs, Fish, and Aquatic Plants
    Toxins 2014, 6, 488-508; doi:10.3390/toxins6020488 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Article Co-occurrence of the Cyanotoxins BMAA, DABA and Anatoxin-a in Nebraska Reservoirs, Fish, and Aquatic Plants Maitham Ahmed Al-Sammak 1,3, Kyle D. Hoagland 2, David Cassada 3 and Daniel D. Snow 3,* 1 Environmental Health, Occupational Health, & Toxicology, Tropical Biological Researches Unit, College of Science, University of Baghdad, Baghdad 10071, Iraq; E-Mail: [email protected] 2 School of Natural Resources, University of Nebraska, Lincoln, NE 68583, USA; E-Mail: [email protected] 3 Nebraska Water Center and School of Natural Resources, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed: E-Mail: [email protected]; Tel.: +1-402-472-7539; Fax: +1-402-472-9599. Received: 12 November 2013; in revised form: 19 December 2013 / Accepted: 17 January 2014 / Published: 28 January 2014 Abstract: Several groups of microorganisms are capable of producing toxins in aquatic environments. Cyanobacteria are prevalent blue green algae in freshwater systems, and many species produce cyanotoxins which include a variety of chemical irritants, hepatotoxins and neurotoxins. Production and occurrence of potent neurotoxic cyanotoxins β-N-methylamino-L-alanine (BMAA), 2,4-diaminobutyric acid dihydrochloride (DABA), and anatoxin-a are especially critical with environmental implications to public and animal health. Biomagnification, though not well understood in aquatic systems, is potentially relevant to both human and animal health effects. Because little is known regarding their presence in fresh water, we investigated the occurrence and potential for bioaccumulation of cyanotoxins in several Nebraska reservoirs.
    [Show full text]
  • Widespread and Differential Neurotoxicity In
    Neurotoxicity Research https://doi.org/10.1007/s12640-021-00330-4 ORIGINAL ARTICLE Widespread and Diferential Neurotoxicity in Venoms from the Bitis Genus of Viperid Snakes Nicholas J. Youngman1 · Richard J. Harris1 · Tam M. Huynh2 · Kristian Coster3 · Eric Sundman3 · Ralph Braun4 · Arno Naude5 · Wayne C. Hodgson2 · Bryan G. Fry1 Received: 24 November 2020 / Revised: 2 January 2021 / Accepted: 5 January 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021 Abstract Research into the neurotoxic activity of venoms from species within the snake family Viperidae is relatively neglected com- pared with snakes in the Elapidae family. Previous studies into venoms from the Bitis genus of vipers have identifed the pres- ence of presynaptic phospholipase A2 neurotoxins in B. atropos and B. caudalis, as well as a postsynaptic phospholipase A2 in B. arietans. Yet, no studies have investigated how widespread neurotoxicity is across the Bitis genus or if they exhibit prey selectivity of their neurotoxins. Utilising a biolayer interferometry assay, we were able to assess the binding of crude venom from 14 species of Bitis to the neuromuscular α-1 nAChR orthosteric site across a wide range of vertebrate taxa mimotopes. Postsynaptic binding was seen for venoms from B. arietans, B. armata, B. atropos, B. caudalis, B. cornuta, B. peringueyi and B. rubida. To further explore the types of neurotoxins present, venoms from the representatives B. armata, B. caudalis, B. cornuta and B. rubida were additionally tested in the chick biventer cervicis nerve muscle preparation, which showed presynaptic and postsynaptic activity for B.
    [Show full text]
  • Systemic Approaches to Modifying Quinolinic Acid Striatal Lesions in Rats
    The Journal of Neuroscience, October 1988, B(10): 3901-3908 Systemic Approaches to Modifying Quinolinic Acid Striatal Lesions in Rats M. Flint Beal, Neil W. Kowall, Kenton J. Swartz, Robert J. Ferrante, and Joseph B. Martin Neurology Service, Massachusetts General Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02114 Quinolinic acid (QA) is an endogenous excitotoxin present mammalian brain, is an excitotoxin which producesaxon-spar- in mammalian brain that reproduces many of the histologic ing striatal lesions. We found that this compound produced a and neurochemical features of Huntington’s disease (HD). more exact model of HD than kainic acid, sincethe lesionswere In the present study we have examined the ability of a variety accompaniedby a relative sparingof somatostatin-neuropeptide of systemically administered compounds to modify striatal Y neurons (Beal et al., 1986a). QA neurotoxicity. Lesions were assessed by measurements If an excitotoxin is involved in the pathogenesisof HD, then of the intrinsic striatal neurotransmitters substance P, so- agentsthat modify excitotoxin lesionsin vivo could potentially matostatin, neuropeptide Y, and GABA. Histologic exami- be efficacious as therapeutic agents in HD. The best form of nation was performed with Nissl stains. The antioxidants therapy from a practical standpoint would be a drug that could ascorbic acid, beta-carotene, and alpha-tocopherol admin- be administered systemically, preferably by an oral route. In the istered S.C. for 3 d prior to striatal QA lesions had no sig- presentstudy we have therefore examined the ability of a variety nificant effect. Other drugs were administered i.p. l/2 hr prior of systemically administered drugs to modify QA striatal neu- to QA striatal lesions.
    [Show full text]
  • High-Dose Methamphetamine Acutely Activates the Striatonigral Pathway to Increase Striatal Glutamate and Mediate Long-Term Dopamine Toxicity
    The Journal of Neuroscience, December 15, 2004 • 24(50):11449–11456 • 11449 Behavioral/Systems/Cognitive High-Dose Methamphetamine Acutely Activates the Striatonigral Pathway to Increase Striatal Glutamate and Mediate Long-Term Dopamine Toxicity Karla A. Mark,1 Jean-Jacques Soghomonian,2 and Bryan K. Yamamoto1 1Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, and 2Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118 Methamphetamine (METH) has been shown to increase the extracellular concentrations of both dopamine (DA) and glutamate (GLU) in the striatum. Dopamine, glutamate, or their combined effects have been hypothesized to mediate striatal DA nerve terminal damage. Although it is known that METH releases DA via reverse transport, it is not known how METH increases the release of GLU. We hypothesized that METH increases GLU indirectly via activation of the basal ganglia output pathways. METH increased striatonigral GABAergic transmission, as evidenced by increased striatal GAD65 mRNA expression and extracellular GABA concentrations in sub- stantia nigra pars reticulata (SNr). The METH-induced increase in nigral extracellular GABA concentrations was D1 receptor-dependent because intranigral perfusion of the D1 DA antagonist SCH23390 (10 ␮M) attenuated the METH-induced increase in GABA release in the SNr. Additionally, METH decreased extracellular GABA concentrations in the ventromedial thalamus (VM). Intranigral perfusion of the GABA-A receptor antagonist, bicuculline (10 ␮M), blocked the METH-induced decrease in extracellular GABA in the VM and the METH- induced increase in striatal GLU. Intranigral perfusion of either a DA D1 or GABA-A receptor antagonist during the systemic adminis- trations of METH attenuated the striatal DA depletions when measured 1 week later.
    [Show full text]
  • Fluorine-18-FPH for PET Imaging of Nicotinic Acetylcholine Receptors
    32. Holman BL. Hcllman RS. Goldsmith SJ, et al. Biodislribution. dosimetry. and clinical 34. Suess E, Huck S, Reither H, Hortnagl H, Angelberger P. Uptake mechanism of evaluation of technetium-99m-ethyl cystcinate dimer in normal subjects and in patients technetium-99m-d. I-HMPAO in cell cultures of the dissociated postnatal rat cerebel with chronic cerebral infarction. J NucíMed 1989:30:1018-1024. lum. J NucíMed 1992:33:108-114. 33. Andersen AR. Technetium-99m-HMPAO: basic kinetic studies of a tracer of cerebral 35. Moretti JL, Caglar M, Weinmann P. Cerebral perfusion imaging tracers for SPECT: blood flow. Cerehrovasc Brain Metab Rev 1989:1:288-318. which one to choose? J NucíMed 1995:36:359-363. Fluorine-18-FPH for PET Imaging of Nicotinic Acetylcholine Receptors Andrew Horti, Ursula Scheffel, Marigo Stathis, Paige Finley, Hayden T. Ravert, Edythe D. London and Robert F. Dannais Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland; and Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins Medical School, Baltimore, Maryland studied extensively. Molecular biological techniques have been Visualization of central nicotinic acetylcholine receptors (nAChRs) applied in determining the amino acid sequences of the subunits with modern PET or SPECT imaging techniques has been ham that compose the receptor (1-3), autoradiographic techniques pered by the lack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics have been used to delineate the anatomical distribution of appropriate for the half-life of the tracer and imaging modality used). nAChRs in brain (4-7} and metabolic mapping studies have This paper describes in vivo binding, kinetics and pharmacology of demonstrated that the specific binding sites labeled in brain a highly potent 18F-labeled analog of epibatidine, (±)-exo-2-(2- with specific radioligands are coupled to functional activity (8).
    [Show full text]
  • 1 3,4-Methylenedioxy
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Diposit Digital de la Universitat de Barcelona 3,4-Methylenedioxy-methamphetamine induces in vivo regional up- regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors Authors: David Pubill, Sara Garcia-Ratés, Jordi Camarasa, Elena Escubedo Address: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Institut de Biomedicina de la UB (IBUB), 08028 Barcelona, Spain Email: D. Pubill: [email protected] S. Garcia: [email protected] J. Camarasa: [email protected] E. Escubedo: [email protected] Corresponding author: Name: David Pubill Address: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Av. Joan XXIII s/n; 08028 Barcelona, SPAIN Tel: (+34) 934024531 Fax: (+34) 934035982 Email: [email protected] 1 Abstract Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxy- methamphetamine (MDMA) has affinity for nAChR and also induces up- regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [3H]paroxetine binding in the cortex and hippocampus measured 24 h after the last dose and these decreases were not modified by the association with NIC.
    [Show full text]
  • PR6 2009.Vp:Corelventura
    Pharmacological Reports Copyright © 2009 2009, 61, 966977 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Review Methamphetamine-induced neurotoxicity: the road to Parkinson’s disease Bessy Thrash, Kariharan Thiruchelvan, Manuj Ahuja, Vishnu Suppiramaniam, Muralikrishnan Dhanasekaran Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, 4306 Walker building, AL 36849 Auburn, USA Correspondence: Muralikrishnan Dhanasekaran, e-mail: [email protected] Abstract: Studies have implicated methamphetamine exposure as a contributor to the development of Parkinson’s disease. There is a signifi- cant degree of striatal dopamine depletion produced by methamphetamine, which makes the toxin useful in the creation of an animal model of Parkinson’s disease. Parkinson’s disease is a progressive neurodegenerative disorder associated with selective degenera- tion of nigrostriatal dopaminergic neurons. The immediate need is to understand the substances that increase the risk for this debili- tating disorder as well as these substances’neurodegenerative mechanisms. Currently, various approaches are being taken to develop a novel and cost-effective anti-Parkinson’s drug with minimal adverse effects and the added benefit of a neuroprotective effect to fa- cilitate and improve the care of patients with Parkinson’s disease. A methamphetamine-treated animal model for Parkinson’s disease can help to further the understanding of the neurodegenerative processes that target the nigrostriatal system. Studies on widely used drugs of abuse, which are also dopaminergic toxicants, may aid in understanding the etiology, pathophysiology and progression of the disease process and increase awareness of the risks involved in such drug abuse. In addition, this review evaluates the possible neuroprotective mechanisms of certain drugs against methamphetamine-induced toxicity.
    [Show full text]