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 serotonin2A receptor signaling. The purpose of the current study is to further understand the mechanisms underlying this desensitization response of serotonin2A receptor signaling in vivo. We now report that desensitization of serotonin2A receptor stimulated-phospholipase C activity in rat frontal cortex induced by olanzapine is dependent on 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. Pretreatment with a JAK2 inhibitor AG490, significantly attenuated the olanzapine-induced reductions in serotonin2A 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 serotonin2A receptor pathway in the hypothalamic paraventricular nucleus mediating increases in plasma hormone levels. AG490 dose-dependently inhibited serotonin2A receptor-stimulated oxytocin and corticosterone release. Taken together, these results suggest that the olanzapine-induced increase in RGS7 expression is mediated by activation of JAK-STAT and is necessary for olanzapine-induced desensitization of serotonin2A receptor-stimulated phospholipase C activity in the frontal cortex but not serotonin2A receptor-stimulated hormone release.