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Neurochem Int

Title:		Blockade and reversal of swimming-induced paralysis in C. elegans by the antipsychotic and D2-type dopamine receptor antagonist azaperone
Author(s):		Refai O; Blakely RD;
Address:		"Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, FL, USA. Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, FL, USA; Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA. Electronic address: rblakely@health.fau.edu"
Journal Title:		Neurochem Int
Year:		2019
Volume:		20180522
Issue:
Page Number:		59 - 68
DOI:		10.1016/j.neuint.2018.05.013
ISSN/ISBN:		1872-9754 (Electronic) 0197-0186 (Print) 0197-0186 (Linking)
Abstract:		"The catecholamine neurotransmitter dopamine (DA) exerts powerful modulatory control of physiology and behavior across phylogeny. Perturbations of DA signaling in humans are associated with multiple neurodegenerative and behavioral disorders, including Parkinson's disease, attention-deficit/hyperactivity disorder, addiction and schizophrenia. In the nematode C. elegans, DA signaling regulates mating behavior, learning, food seeking and locomotion. Previously, we demonstrated that loss of function mutations in the dat-1 gene that encodes the presynaptic DA transporter (DAT-1) results in a rapid cessation of movement when animals are placed in water, termed Swimming Induced Paralysis (Swip). Loss of function mutations in genes that support DA biosynthesis, DA vesicular packaging and DA action at the extrasynaptic D2-type DA receptor DOP-3 suppress Swip in dat-1 animals, consistent with paralysis as arising from excessive DA signaling. Although animals grown on the vesicular monoamine transporter antagonist reserpine diminish Swip, the drug must be applied chronically, can impact the signaling of multiple biogenic amines, and has been reported to have penetrant, off-target actions. Here, we demonstrate that the antipsychotic drug azaperone potently and rapidly suppresses Swip behavior in either dat-1 mutants, as well as in wildtype animals treated with the DAT-1 antagonist nisoxetine, with genetic experiments consistent with DOP-3 antagonism as the mechanism of Swip suppression. Reversal of Swip in previously paralyzed dat-1 animals by azaperone application demonstrates an otherwise functionally-intact swimming circuit in these mutants. Finally, whereas azaperone suppresses DA-dependent Swip, the drug fails to attenuate the DA-independent paralysis induced by betaPEA, aldicarb or genetic disruption of gamma-aminobutyric acid (GABA) signaling. We discuss our findings with respect to the use of azaperone as a potent and selective tool in the identification and analysis of presynaptic mechanisms that regulate DA signaling"
Keywords:		"Animals Animals, Genetically Modified/genetics Antipsychotic Agents/*pharmacology Azaperone/*pharmacology Caenorhabditis elegans Caenorhabditis elegans Proteins/drug effects/metabolism Dopamine/metabolism Dopamine Antagonists/pharmacology Dopamine Plasma;"
Notes:		"MedlineRefai, Osama Blakely, Randy D eng R01 MH095044/MH/NIMH NIH HHS/ Research Support, N.I.H., Extramural England 2018/05/26 Neurochem Int. 2019 Feb; 123:59-68. doi: 10.1016/j.neuint.2018.05.013. Epub 2018 May 22"