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ABSTRACT: RATIONAL: Although it has been recognized that inhibition of calcineurin induced depressive-like behavior, the underlying neural mediators have not yet been identified. Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates protein synthesis in synapses, has been demonstrated to be involved in the rapid antidepressant effects of ketamine. OBJECTIVE: To investigate a potential role of mTOR signaling pathway which interferes with depressive-like behavior induced by calcineurin blockade and to determine the neurobiological mechanisms underlying mood-related disorders. METHODS: Calcineurin inhibitor cyclosporine A (CsA) and tacrolimus (FK506) were microinjected into the medial prefrontal cortex (mPFC) in rats, and the depressive-like behavior was measured in sucrose preference test and forced swim test. Additionally, mTOR activity was tested by the levels of phosphorylation of p70s6 kinase (p70s6k) and 40S ribosomal protein S6 (rps6). RESULTS: Chronic microinjection of CsA or FK506 into mPFC increased depressive-like behaviors and decreased mTOR activity, but acute CsA or FK506 had no effects on both behavioral phenotype and mTOR activity. Furthermore, activation of mTOR by NMDA reversed the depressive-like behavior induced by chronic CsA or FK506 administration. Moreover, inhibition of mTOR by rapamycin reversed the antidepressant effects of ketamine. Finally, traditional antidepressant venlafaxine prevented the depressive-like performance induced by chronic CsA or FK506 treatment. CONCLUSION: These findings indicate that calcineurin-inhibition-induced depressive-like behavior is mediated by blockade of the mTOR signaling pathway and raise the possibility that stimulation of specific brain mTOR may be sufficient to decrease risk of affective disorders in patients treated with calcineurin inhibitor.