title: Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans.
abstract: Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.
authors.affiliation: Departmento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil. patriciareckziegel@hotmail.com.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Reckziegel
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Caito
authors.affiliation: Departmento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Priscila
authors.initials: P
authors.lastname: Gubert
authors.affiliation: Departmento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Félix Alexandre Antunes
authors.initials: FA
authors.lastname: Soares
authors.affiliation: Departmento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Roselei
authors.initials: R
authors.lastname: Fachinetto
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. michael.aschner@einstein.yu.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D010063:Ovum / Q000187:drug effects; D010300:Parkinson Disease / Q000503:physiopathology; D012110:Reserpine / Q000633:toxicity*
chemical_list: D029742:Caenorhabditis elegans Proteins; C532156:DAT-1 protein, C elegans; D050483:Dopamine Plasma Membrane Transport Proteins; D049452:Green Fluorescent Proteins; D012110:Reserpine; D004298:Dopamine
keywords: Dopamine transporter; Neurodegeneration; Neurotoxicity; Parkinson’s disease; Worm