Novel Role of the JAK-STAT Pathway in Mediating the Effects of Atypical Antipsychotics on 5-HT2A Receptor Signaling

Abstract

The therapeutic benefits of atypical antipsychotics are proposed to be mediated by antagonism and subsequent desensitization of 5-HT2A receptor signaling; however, the mechanisms underlying this desensitization response are not yet understood. We hypothesize that the desensitization of 5-HT2A receptors induced by atypical antipsychotics is dependent on activation of the JAK-STAT pathway. To test this hypothesis, we used a cell line, A1A1v cells, that natively expresses 5-HT2A receptor signaling system, and further confirmed the findings in rats. In A1A1v cells, we confirmed that treatment with both olanzapine and clozapine desensitizes 5-HT2A receptor signaling. Furthermore, olanzapine treatment also increased RGS7 mRNA and protein levels which were dependent on activation of JAK-STAT pathway. Similar results were found with MDL100907, a specific 5HT2A receptor antagonist; RGS7 protein and mRNA levels were increased along with activation of the JAK-STAT pathway, suggesting that antagonism of 5-HT2A receptors is sufficient to induce these changes. In addition, we also found an increase in STAT3 binding to the putative RGS7 promoter region with olanzapine treatment suggesting that the increase in RGS7 expression could be directly mediated by the JAK-STAT pathway. An increase in RGS protein could mediate desensitization of 5-HT2A receptor signaling by its GAP activity. Lastly, inhibition of the JAK-STAT pathway significantly attenuated olanzapine-induced desensitization of 5-HT2A receptor signaling in A1A1v cells. Similar findings were also observed in rats treated with olanzapine for 7 days. We found a decrease in 5-HT2A receptor-stimulated PLC activity in the frontal cortex which was dependent on activation of JAK-STAT pathway. Consistent with the cell culture data, the olanzapine-induced increase in RGS7 proteins and mRNA levels were dependent on activation of the JAK-STAT pathway. Olanzapine treatment significantly reduced plasma levels of oxytocin, adrenocorticotrophic hormone (ACTH), and corticosterone. Surprisingly, 5-HT2A receptor-stimulated oxytocin and corticosterone levels were also decreased in a dose-dependent manner by the JAK inhibitor whereas ACTH levels were not altered. Further studies are needed to investigate the role of the JAK-STAT pathway in the regulation of hormone levels. Taken together, these results from experiments in cells in culture and in rats suggest that increases in RGS7 expression via increased activation of the JAK-STAT pathway are necessary for antipsychotic-induced desensitization of 5-HT2A receptor signaling.