Abstract # 1750 Rapamycin inhibits antidepressant effects of leucine in lipopolysaccharide-treated mice

We previously showed that leucine supplementation abrogates lipopolysaccharide (LPS)-induced depression-like behavior by competing with the LAT1-dependent transport of kynurenine into the brain. Since leucine activates mTOR in its target cells the objective of the present series of experiments was to determine whether the antidepressant activity of leucine is mediated by activation of mTOR. Using Western blot we first confirmed that leucine (500 mg/kg IP) activates mTOR in the prefrontal cortex 1 hr after treatment, as measured by phosphorylation of AKT, MAP kinase, and mTOR. We then administered rapamycin (0.75 mg/kg IP) before leucine (500 mg/kg IP) and LPS (0.83 mg/kg IP) to CD-1 mice for behavioral experiments. Leucine abrogated LPS-induced reduction in sucrose preference and increased immobility in the forced swim test. These effects were reversed by rapamycin pretreatment. Because leucine utilization by its target cells requires mTOR-mediated upregulation of LAT1 we examined the possibility that rapamycin blocks the effects of leucine by interfering with this mechanism. Livers and hippocampi of mice treated with rapamycin, leucine and LPS were collected at the end of the experiment and expression of LAT1 was analyzed by qRT-PCR. Administration of LPS and leucine in association increased LAT1 expression in both tissues and this effect was blocked by pretreatment with rapamycin. These findings demonstrate the importance of blood-brain barrier transport mechanisms in inflammation-induced depression. Supported by NIH-NIMH (MH104694) and MDACC.