title: Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release.
abstract: Chronic treatment with olanzapine causes desensitization of serotonin 2A receptor signaling. The purpose of the current study was to further understand the mechanisms underlying this desensitization response of serotonin 2A receptor signaling in vivo. We report that desensitization of serotonin 2A receptor stimulated-phospholipase C activity in rat frontal cortex induced by olanzapine is dependent on the activation of the JAK-STAT pathway. Olanzapine treatment for 7 days significantly increased the levels of the regulator of G protein signaling (RGS7) protein, RGS7 mRNA levels, and activation of JAK2 in rat frontal cortex. Pre-treatment with a JAK2 inhibitor AG490, significantly attenuated the olanzapine-induced reductions in serotonin 2A receptor-stimulated phospholipase C activity and prevented the olanzapine-induced increases in RGS7 mRNA and protein levels. In contrast, inhibition of the JAK-STAT pathway with AG490 did not reverse the olanzapine-induced desensitization of the serotonin 2A receptor pathway in the hypothalamic paraventricular nucleus mediating increases in plasma hormone levels. AG490 dose-dependently inhibited serotonin 2A receptor-stimulated oxytocin and corticosterone release. These results suggest that the olanzapine-induced increase in RGS7 expression is mediated by the activation of JAK-STAT and is necessary for olanzapine-induced desensitization of serotonin 2A receptor-stimulated phospholipase C activity in the frontal cortex but not serotonin 2A receptor-stimulated hormone release.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Singh
authors.forename: C
authors.initials: C
authors.lastname: Jia
authors.forename: F
authors.initials: F
authors.lastname: Garcia
authors.forename: G A
authors.initials: GA
authors.lastname: Carrasco
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: N A
authors.initials: NA
authors.lastname: Muma
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D015153:Blotting, Western; D003345:Corticosterone / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006728:Hormones / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D008297:Male; D000077152:Olanzapine; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology; D020710:RGS Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D010738:Type C Phospholipases / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000324:Adrenocorticotropic Hormone; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003345:Corticosterone; D004791:Enzyme Inhibitors; D006728:Hormones; D053614:Janus Kinase 2; D000077152:Olanzapine; D020710:RGS Proteins; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D050796:STAT3 Transcription Factor; D017367:Selective Serotonin Reuptake Inhibitors; D010738:Type C Phospholipases; D020032:Tyrphostins; C115771:Rgs7 protein, rat; C494088:Stat3 protein, rat; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507927:Jak2 protein, rat