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Haloperidol Interactions with the dop-3 Receptor in Caenorhabditis elegans

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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.

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Acknowledgments

We specially acknowledge the collaboration of the colleagues Mahfuzur Miah, Ayodele Jacob Akinyemi, and Tao Ke for technical support.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. Aschner M was supported in part by grants from the National Institute of Environmental Health Sciences (NIEHS), R01 ES07331, and R01 ES10563.

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Authors and Affiliations

  1. Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Camobi, Santa Maria, RS, 97105-900, Brazil

    Bárbara Nunes Krum & Roselei Fachinetto

  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Forccheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Bárbara Nunes Krum, Airton C. Martins Jr, Libânia Queirós, Beatriz Ferrer, Félix Alexandre Antunes Soares & Michael Aschner

  3. Department of Biology and CESAM (Centre for Environmental and Marine Studies), University of Aveiro, 3810-193, Aveiro, Portugal

    Libânia Queirós

  4. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37240, USA

    Ginger L. Milne

  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

    Félix Alexandre Antunes Soares

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  1. Bárbara Nunes Krum
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Contributions

Krum BN: conceptualization, investigation, writing- original draft preparation, conducted all the experiments with the support of Martins AC, Queirós L, Ferrer B, and Milne GL. Soares FAA: conceptualization, writing - review and editing, visualization. Fachinetto R: supervision, writing - review & editing. Aschner M: conceptualization, supervision, resources, writing - review & editing.

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Correspondence to Michael Aschner.

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Krum, B.N., Martins, A.C., Queirós, L. et al. Haloperidol Interactions with the dop-3 Receptor in Caenorhabditis elegans. Mol Neurobiol 58, 304–316 (2021). https://doi.org/10.1007/s12035-020-02124-9

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