Antipsychotic drugs activate the C. elegans akt pathway via the DAF-2 insulin/IGF-1 receptor.
The molecular modes of action of antipsychotic drugs are poorly understood beyond their effects at the dopamine D2 receptor. Previous studies have placed Akt signaling downstream of D2 dopamine receptors, and recent data have suggested an association between psychotic illnesses and defective Akt signaling. To characterize the effect of antipsychotic drugs on the Akt pathway, we used the model organism C. elegans, a simple system where the Akt/forkhead box O transcription factor (FOXO) pathway has been well characterized. All major classes of antipsychotic drugs increased signaling through the insulin/Akt/FOXO pathway, whereas four other drugs that are known to affect the central nervous system did not. The antipsychotic drugs inhibited dauer formation, dauer recovery, and shortened lifespan, three biological processes affected by Akt signaling. Genetic analysis showed that AKT-1 and the insulin and insulin-like growth factor receptor, DAF-2, were required for the antipsychotic drugs to increase signaling. Serotonin synthesis was partially involved, whereas the mitogen activated protein kinase (MAPK), SEK-1 is a MAP kinase kinase (MAPKK), and calcineurin were not involved. This is the first example of a common but specific molecular effect produced by all presently known antipsychotic drugs in any biological system. Because untreated schizophrenics have been reported to have low levels of Akt signaling, increased Akt signaling might contribute to the therapeutic actions of antipsychotic drugs.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana, USA.
Kathrine R
KR
Weeks
Donard S
DS
Dwyer
Eric J
EJ
Aamodt
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D003024:Clozapine / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000502:physiology; D007814:Larva / Q000187:drug effects; D000077152:Olanzapine; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000187:drug effects*; D011972:Receptor, Insulin / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014268:Trifluoperazine / Q000494:pharmacology
D014150:Antipsychotic Agents; D029742:Caenorhabditis elegans Proteins; D001569:Benzodiazepines; D014268:Trifluoperazine; D006160:Guanosine Triphosphate; C107483:DAF-2 protein, C elegans; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D003024:Clozapine; D000077152:Olanzapine