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Activation of mammalian target of rapamycin (mTOR) and inhibition of glycogen synthase kinase-3\u03b2 (GSK3\u03b2) have been implicated in its putative mechanisms of action. These proteins are integral components of the insulin signaling pathway, which may serve as a critical co-regulator of drug action. Utilizing an animal model of tricyclic antidepressant resistance, we investigated the relationship between insulin signaling and antidepressant response to lithium augmentation. Pre-treatment with adrenocorticotropic hormone (ACTH 100\u2009\u00b5g\/day i.p.) for 14 days effectively blocked the immobility-reducing effects of an acute dose of imipramine (10\u2009mg\/kg i.p.) in the forced swim test (FST). Lithium augmentation (100\u2009mg\/kg i.p.) rescued the antidepressant-like effects of imipramine in this model. Total and phosphorylated (<jats:italic>p<\/jats:italic>) levels of protein kinase B (Akt), mTOR, and GSK3\u03b2 protein were quantified in the infralimbic cortex (ILPFC) following FST stress via Western blot. Levels of mTOR and <jats:italic>p<\/jats:italic>mTOR were further quantified in isolated peripheral blood mononuclear cells (PBMCs) following insulin stimulation (10\u2009mg\/mL for 5\u2009min) via ELISA. Elevated levels of phosphorylated insulin signaling proteins were present in the ILPFC of ACTH-pretreated animals that received both imipramine and lithium, together with a concurrent increase in mTOR activation in PBMCs. Large correlations were observed between immobility time and insulin-stimulated mTOR levels in PBMCs. We propose that PBMC insulin challenge may be a useful probe for predicting antidepressant response to lithium administration, and potentially other therapies acting via similar mechanisms of action.<\/jats:p>","DOI":"10.1038\/s41398-019-0434-5","type":"journal-article","created":{"date-parts":[[2019,3,15]],"date-time":"2019-03-15T23:21:44Z","timestamp":1552692104000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Insulin-stimulated mTOR activation in peripheral blood mononuclear cells associated with early treatment response to lithium augmentation in rodent model of antidepressant-resistance"],"prefix":"10.1038","volume":"9","author":[{"given":"Adam J.","family":"Walker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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