Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex

NEUROPHARMACOLOGY

卷:53

Article

Muma, N. A. ; Singh, R. K. ; Vercillo, M. S. ; D'Souza, D. N. ; Zemaitaitis, B. ; Garcia, F. ; Damjanoska, K. J. ; Zhang, Y. ; Battaglia, G. ; de Kar, L. D. Van

关键词: antipsychotic;    serotonin 2A receptor;    in vivo;   

DOI  :  10.1016/j.neuropharm.2007.06.019

来源: Elsevier

【 摘 要 】

The mechanisms underlying desensitization of serotonin 2A (5-HT2A) receptor signaling by antagonists are unclear but may involve changes in gene expression mediated via signal transduction pathways. In cells in culture, olanzapine causes desensitization of 5-HT2A receptor signaling and increases the levels of regulators of G protein signaling (RGS) 7 protein dependent on phosphorylation/activation of the Janus kinase 2 (Jak2)/signal transducers and activators of transcription 3 (Stat3) signaling pathway. In the current study, the 5-HT2A receptor signaling system in rat frontal cortex was examined following 7 days of daily treatment with 0.5, 2.0 or 10.0 mg/kg i.p. olanzapine. Olanzapine increased phosphorylation of Stat3 in rats treated daily with 10 mg/kg olanzapine and caused a dose-dependent desensitization of 5-HT2A receptor-mediated phospholipase C activity. There were dose-dependent increases in the levels of membrane-associated 5-HT2A receptor, G(alpha 11) and G(alpha q) protein levels but no changes in the Go protein levels. With olanzapine treatment, RGS4 protein levels increase in the membrane-fraction and decrease in the cytosolic fraction by similar amounts suggesting a redistribution of RGS4 protein within neurons. RGS7 protein levels increase in both the membrane and cytosolic fractions in rats treated daily with 10 mg/kg olanzapine. The olanzapine-induced increase in Stat3 activity could underlie the increase in RGS7 protein expression in vivo as previously demonstrated in cultured cells. Furthermore, the increases in membrane-associated RGS proteins could play a role in desensitization of signaling by terminating the activated G(alpha q/11) proteins more rapidly. (C) 2007 Elsevier Ltd. All rights reserved.

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