title: Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus.
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.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Karmacharya
authors.forename: Spencer K
authors.initials: SK
authors.lastname: Lynn
authors.forename: Sarah
authors.initials: S
authors.lastname: Demarco
authors.forename: Angelica
authors.initials: A
authors.lastname: Ortiz
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Miriam Y
authors.initials: MY
authors.lastname: Lundy
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xie
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Miller
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Buttner
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001679:Biogenic Amines / Q000378:metabolism; D017173:Caenorhabditis elegans; D003024:Clozapine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010058:Oviposition / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D000095383:Trace Amine-Associated Receptors
chemical_list: D014150:Antipsychotic Agents; D001679:Biogenic Amines; D003024:Clozapine; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors