RRC ID 56212
著者 Refai O, Blakely RD.
タイトル Blockade and reversal of swimming-induced paralysis in C. elegans by the antipsychotic and D2-type dopamine receptor antagonist azaperone.
ジャーナル Neurochem Int
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 βPEA, aldicarb or genetic disruption of γ-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.
巻・号 123
ページ 59-68
公開日 2019-2-1
DOI 10.1016/j.neuint.2018.05.013
PII S0197-0186(18)30169-4
PMID 29800604
PMC PMC6250597
MeSH Animals Animals, Genetically Modified / genetics Antipsychotic Agents / pharmacology* Azaperone / pharmacology* Caenorhabditis elegans Caenorhabditis elegans Proteins / drug effects Caenorhabditis elegans Proteins / metabolism Dopamine / metabolism Dopamine Antagonists / pharmacology Dopamine Plasma Membrane Transport Proteins / drug effects* Dopamine Plasma Membrane Transport Proteins / metabolism Fluoxetine / analogs & derivatives Fluoxetine / pharmacology Reserpine / pharmacology Signal Transduction / drug effects* Signal Transduction / genetics
IF 3.994
引用数 1
リソース情報
線虫 tm5915