RRC ID 46140
著者 Karmacharya R, Lynn SK, Demarco S, Ortiz A, Wang X, Lundy MY, Xie Z, Cohen BM, Miller GM, Buttner EA.
タイトル Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus.
ジャーナル Brain Res
Abstract Clozapine is an antipsychotic medication with superior efficacy in treatment refractory schizophrenia. The molecular basis of clozapine's therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapine's biological effects. Clozapine stimulated egg laying in C. elegans in a dose-dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyramine biosynthesis. To test the implications of this finding across species, we explored whether trace amine systems modulate clozapine's behavioral effects in mammals by studying trace amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased prepulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of trace amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore-unknown role for trace amine systems in clozapine-mediated effects across two species: C. elegans and mice.
巻・号 1393
ページ 91-9
公開日 2011-6-1
DOI 10.1016/j.brainres.2011.04.010
PII S0006-8993(11)00678-0
PMID 21529784
PMC PMC3107707
MeSH Animals Antipsychotic Agents / pharmacology* Behavior, Animal / drug effects* Biogenic Amines / metabolism Caenorhabditis elegans* Clozapine / pharmacology* HEK293 Cells Humans Mice Mice, Inbred C57BL Mice, Knockout* Oviposition / drug effects Receptors, G-Protein-Coupled / genetics Schizophrenia / drug therapy Signal Transduction / drug effects Species Specificity
IF 2.733
引用数 11
WOS 分野 NEUROSCIENCES
リソース情報
線虫 tm1815 tm2913 tm1062 tm2261 tm1846 tm351