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• W2364039600 abstract "Background:Mammalian target of rapamycin (mTOR) is a serine/ threonine kinase,whose effect can be blocked by rapamycin. The main effect of mTOR signaling pathway is to promote cell growth by regulating gene transcription and protein translation. mTOR evidently plays an important role in central nerve system,in which protein synthesis for synaptic plasticity mediated by this pathway is essential for memory formation. Addiction is a long-term neuroadaptation process with high rate of relapse when addicts are exposed to the drug,drug related cues and pressure. Previous study has demonstrated that mTOR signaling pathway involved in the drug rewarding and seeking. However,whether mTOR signaling pathway plays a role in relapse to drug seeking after withdrawal is not investigated. Objective:Using the model of reinstatement of cocaine self-administration after withdrawal in rats to investigate the role of mTOR signaling pathway in relapse of drug seeking. Methods:1) Male,Sprague-Dawley rats self-administered(iv) cocaine in the presence of discrete conditioned cues (tone+light) in daily 3-h sessions for ten days. After extinction,rats were exposed to drug related cues in the reinstatement test. The levels of phosphorylated p70s6k in core and shell of nucleus accumbens (NAc) in rats after exposure were examined by Western blot and were compared with the levels in the rats with no reinstatement test. 2) In cue-induced reinstatement test,rats were microinjected the rapamycin into NAc core or shell 30 min before drug-related cues exposure. Response to active nose poke in the reinstatement test was recorded. The levels of phosphorylated p70s6k in NAc core and shell in rats after exposure were also examined. 3)Rats were trained for cocaine self-administration. After extinction,rats underwent reinstatement test induced by cocaine priming,and the mTOR inhibitor rapamycin were microinjected into NAc core or shell of 30min before priming. Response to active nose poke in the reinstatement test was recorded. 4) During the cocaine self-administration training,rats were received rapamycin microinjection into NAc core or shell after reaching stable cocaine self-administration. In the next day,the number of cocaine infusion was recorded to observe the effect of rapamycin on the cocaine reforcing effect. Results:Drug-related cues exposure induced reinstatement enhanced the phosphorylated p70s6k level in NAc core but not in shell. The level of tolal p70s6k had no change. Inhibition of the activated mTOR signaling pathway by microinjection of rapamycin into NAc core attenuated the cue-induced reinstatement of cocaine self-administration compared with vehicle injection in rats,while the NAc shell microinjection has no effects. Results of Westen blot showed that the level of phosphorylated p70s6k in NAc core was decresed in the rats with rapamycin infusion into NAc core,while no decreasing was observed in NAc shell. Total p70s6k levels were no change in both brain areas. Microinjection of rapamycin into NAc shell can significantly attenuate the reinstatement of cocaine self-administration induced by cocaine priming compared with vehicle microinjection in rats,while the NAc core rapamycin microinjection has no effects. These results suggested that mTOR signaling pathway activation was involved in the reinstatement,and inhibiting mTOR could inhibit the reinstatement to cocaine seeking. In addition,microinjection of rapamycin into NAc core or shell did not affect the acquired cocaine self-administration,indicating that rapamycin did not decrease the cocaine reforcing effect. Conclusion:The presented study found that rapamycin microinjention into NAc shell and core can effectively block the reinstatement of cocaine self-administration induced by cocaine-priming and drug-related cue,respectively,by inhibiting the mTOR signaling pathway in NAc. It demonstrated that mTOR signaling pathway plays an important role in the relapse to drug seeking after withdrawal. These findings extend our understanding of the neurobiology of drug addiction,and provide evidence for the development of therapeutic treatment of relapse prevention." @default.
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• W2364039600 date "2009-01-01" @default.
• W2364039600 modified "2023-09-22" @default.
• W2364039600 title "THE ROLE OF MTOR SIGNALING PATHWAY IN THE REINSTATEMENT OF COCAINE SELF-ADMINISTRATION IN RATS" @default.
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