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 |