Haloperidol Interactions with the dop-3 Receptor in Caenorhabditis elegans
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Haloperidol Interactions with the dop-3 Receptor in Caenorhabditis elegans Bárbara Nunes Krum 1,2 & Airton C. Martins Jr 2 & Libânia Queirós 2,3 & Beatriz Ferrer 2 & Ginger L. Milne 4 & Félix Alexandre Antunes Soares 2,5 & Roselei Fachinetto 1 & Michael Aschner 2 Received: 14 July 2020 / Accepted: 5 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Haloperidol is a typical antipsychotic drug commonly used to treat a broad range of psychiatric disorders related to dysregulations in the neurotransmitter dopamine (DA). DA modulates important physiologic functions and perturbations in Caenorhabditis elegans (C. elegans) and, its signaling have been associated with alterations in behavioral, molecular, and morphologic properties in C. elegans. Here, we evaluated the possible involvement of dopaminergic receptors in the onset of these alterations followed by haloperidol exposure. Haloperidol increased lifespan and decreased locomotor behavior (basal slowing response, BSR, and locomotion speed via forward speed) of the worms. Moreover, locomotion speed recovered to basal conditions upon haloperidol withdrawal. Haloperidol also decreased DA levels, but it did not alter neither dop-1, dop-2, and dop-3 gene expression, nor CEP dopaminergic neurons’ morphology. These effects are likely due to haloperidol’s antagonism of the D2-type DA receptor, dop-3. Furthermore, this antagonism appears to affect mechanistic pathways involved in the modulation and signaling of neurotransmitters such as octopamine, acetylcholine, and GABA, which may underlie at least in part haloperidol’s effects. These pathways are conserved in vertebrates and have been implicated in a range of disorders. Our novel findings demonstrate that the dop-3 receptor plays an important role in the effects of haloperidol. Keywords Basal slowing response . Dopamine signaling . Lifespan . Locomotor behavior . Neurotransmitter . Worm
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02124-9) contains supplementary material, which is available to authorized users. * Michael Aschner [email protected] 1
Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Camobi, Santa Maria, RS 97105-900, Brazil
2
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Forccheimer 209, 1300 Morris Park Avenue, Bronx, NY 10461, USA
3
Department of Biology and CESAM (Centre for Environmental and Marine Studies), University of Aveiro, 3810-193 Aveiro, Portugal
4
Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USA
5
Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Camobi, Santa Maria, RS 97105-900, Brazil
The powerful genetic model Caenorhabditis elegans (C. elegans) is frequently used in research to explore mechanistic action of drugs, new drug targets, and animal b
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