The Significance of aFGF and mTOR Signal in VTA-Nucleus Accumbens of Methamphetamine-Sensitized Mice

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

The aim of this project is to investigate the role of acidic FGF (fibroblast growth factor-1) and mTOR signal pathway in methamphetamine (METH) addiction. The main reason to propose this study is based on our pioneer study that found a significant increase in amount of mTOR (also the phospho-mTOR/Ser2448) along with down-stream 4E-BP and p70S6K phosphorylation in the nucleus accumbens (NAc) of METH behaviorally sensitized mice (a phenomenon refers to an up-regulation of locomotor activity or stereotypy due to repetitive METH injection; also mimic a situation of compulsive drug use in human addicts). In addition, via dual proteomics and microRNA analyses, we observed an increase in aFGF protein in the ventral tegmental area (VTA) along with a decrease in miR-199a and let-7 family in METH-sensitized mice. Since miR-199a could target the 3’-UTR of aFGF to suppress its protein translation, a reciprocal alteration of aFGF and miR-199a implicates this growth factor could be disinhibited upon chronic METH treatment, leading to abnormal behavioral phenotype and neuroplasticity. It is indeed we observed an increased dendritic arborization in the VTA, detected by Golgi stain, in METH sensitized animals. In addition, mTOR inhibitor, rapamycin co-administration with daily METH treatment could affect not only the development of METH initiation, but behavioral expression, suggesting the mTOR-mediated signaling participates both developmental stages of METH sensitization. Considering the mTOR and mTORC1 (mTOR complex 1)-dependent 4E-BP and p70S6K signaling accounts for a translational signal, critical in the synaptic protein synthesis and determines the neural plasticity in the CNS. Alteration in mTOR and 4E-BP/p70S6K suggests chronic METH triggers a protein translation process in the NAc during the late stage (behavioral expression) of METH sensitization. It is well-known that VTA-NAc mesolimbic dopamine plays a key role in rewarding and also drug addiction, current finding of aFGF/miR-199a change in the VTA and mTOR/4E-BP/p70S6K in the NAc strongly suggest a vigorous growth factor mediated cellular event (possibly the mTOR-mediated translational signaling) might underlie the METH action and determine the pathological development of mesolimbic system. To delineate the role of aFGF and mTOR in the process of METH behavioral sensitization, we propose the following studies: (1) investigate the role of aFGF in the VTA on METH behavioral initiation (1st year); (2) explore the interrelationship between aFGF and miR-199a and understand the impact of miR-199a (also let-7 family that was identified by previous miRNA array) on METH sensitization (1st and 2nd year); (3) examine if mTOR accounts for the up- (protein synthesis) or down-stream (FGFR1-mediated signal) regulator(s) of aFGF in the VTA during the METH sensitization (2nd year); (4) explore the significance of mTOR/4E-BP/p70S6K signals in the NAc on behavioral expression to METH (2nd and 3rd year) and (5) due to the role of mTOR-mediated translational signal in dendritic plasticity, we will identify the mTOR-dependent mRNAs (so called ‘TOP mRNAs’) in both VTA and NAc and their role in behavioral phenotype and morphological change (pathological plasticity) (3rd year). It is believed through these step-by-step approaches, we will unlock the essential protein(s) in particular brain region for their role in development of METH sensitization.

Project IDs

Project ID:PC10301-0900
External Project ID:NSC101-2320-B182-040-MY3
StatusFinished
Effective start/end date01/08/1431/07/15

Keywords

  • methamphetamine
  • drug addiction
  • behavioral sensitization
  • mTOR
  • protein translation
  • microRNA
  • ventral tegmental area
  • nucleus accumbens
  • acidic FGF
  • miR-199a
  • let-7
  • lenti-virus

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