Behavioral effects of clozapine: Involvement of trace amine pathways in C. elegans and M. musculus
| Autor: | Zhihua Xie, Rakesh Karmacharya, Edgar A. Buttner, Gregory M. Miller, Miriam Y. Lundy, Angelica Ortiz, Xin Wang, Sarah E. DeMarco, Bruce M. Cohen, Spencer K. Lynn |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Biogenic Amines
medicine.medical_specialty medicine.drug_class Oviposition medicine.medical_treatment Atypical antipsychotic Pharmacology Biology Article Receptors G-Protein-Coupled Mice Species Specificity Biogenic amine Internal medicine TAAR1 medicine Animals Humans Caenorhabditis elegans Antipsychotic Clozapine Molecular Biology Trace amine Trace amine-associated receptor Mice Knockout chemistry.chemical_classification Behavior Animal General Neuroscience Typical antipsychotic Mice Inbred C57BL HEK293 Cells Endocrinology chemistry Schizophrenia Neurology (clinical) Antipsychotic Agents Signal Transduction Developmental Biology medicine.drug |
| Zdroj: | Brain Research. 1393:91-99 |
| ISSN: | 0006-8993 |
| DOI: | 10.1016/j.brainres.2011.04.010 |
| Popis: | 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 pre-pulse 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. |
| Databáze: | OpenAIRE |
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