Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans

• Published in: Archives of toxicology Vol. 90; no. 3; pp. 633 - 645
• Main Authors: Reckziegel, Patrícia, Chen, Pan, Caito, Sam, Gubert, Priscila, Soares, Félix Alexandre Antunes, Fachinetto, Roselei, Aschner, Michael
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2016; Springer Nature B.V
• Subjects: Animals; Animals, Genetically Modified; Biomedical and Life Sciences; Biomedicine; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cellular biology; Defecation - drug effects; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine - pharmacology; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Drug therapy; Environmental Health; Female; Gene Expression Regulation - drug effects; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Neurodegeneration; Occupational Medicine/Industrial Medicine; Organ Toxicity and Mechanisms; Ovum - drug effects; Parkinson Disease - physiopathology; Pharmacology/Toxicology; Reserpine - toxicity; Toxicity; Dopamine transporter; Neurotoxicity; Worm; Neurodegeneration; Parkinson’s disease
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-015-1451-7

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.