| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 98 === Autophagy is a homeostatic, carefully regulated, and dynamic process for intracellular recycling of bulk proteins and aging organelles and lipids. A growing body of evidence now suggests that alteration or dysfunction of autophagy cause accumulation of abnormal proteins and damaged organelles, thereby leading to neurodegerative disease. The therapeutic actions of lithium and rapamycin may be related to its activity to increase autophagy, then inhibition of mTOR may be a potential new therapy for affective disorders. However, to study precisely mechanisms and signal pathway of rapamycin on antidepressant effects was not complete now. To explore this possibility, the present study tested rapamycin in sub-chronic and chronic doses administration schedules in depressive-like animal models validated to screen antidepressant action. The signaling pathways of mTOR-autophagy, or –S6K1, and AKT-Bcl2/Bax were investigated by rapamycin administration in hippocampus of depressive-like rats.Methods: withdrawal from escalating doses of methamphetamine (1-5 mg/kg/day) for 7 days (sub-chronic) and 21 days (chronic) produced an animal model of depressive-like effects. Rapamycin (I mg/kg) treated during the methamphetamine withdrawal by daily or the other day. The behavioral effects which were the core depressive syndromes were tested by novelty-suppressed feeding (NSF, a depressive/anxiety behavior) and sucrose preference (an anhedonia effect). The Western blot test was to detect the signaling pathway expression.Results: Sub-chronic and chronic administration of rapamycin significantly improved the depressive-like and anedonia behaviors. The protein expressions of mTOR and S6K1 were over expressed in hippocampus of depressive-like animals, rapamycin reversed the effects. The LC3-II (a marker of autophagy), AKT, and Bcl2/Bax activation protein were attenuated in hippocampus of depressive-like rats. These effects were recovered by treatment of rapamycin during the methamphetamine withdrawal.Conclusion: The present study demonstrates an antidepressant-like effect of rapamycin in two behavioral tests in depressive-like animal. It is therefore suggested that mTOR inhibition and AKT-Bcl2 activation may be potential new targets for the treatment of affective disorders. Further studies are now planned to explore correlations between behavioral effects and interactions with other intracellular pathways related to affective disorders.
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