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Regulation of Cytoskeletal Remodeling Proteins in the Ventral Tegmental Area by Morphine, Stress, and TORC2
Author(s) -
Kaska Sophia,
Brunk Rebecca,
Kechner Megan,
MazeiRobison Michelle
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.985.12
Subject(s) - ventral tegmental area , actin cytoskeleton , cytoskeleton , microbiology and biotechnology , morphine , cofilin , neuroscience , biology , dopamine , pharmacology , dopaminergic , cell , biochemistry
Drug addiction and depression are two co‐morbid diseases that have a substantial burden on society. Increasing evidence suggests that dysfunction of the reward circuit could underlie both disorders. In support of this, chronic morphine and chronic social defeat stress (CSDS) have been shown to induce similar changes in ventral tegmental area (VTA) DA neuronal morphology. Specifically, our previous work demonstrated a morphine‐induced decrease in VTA DA size that was mammalian target of rapamycin complex 2 (TORC2) signaling‐dependent. Similarly, preliminary evidence from our lab suggests that mice that are susceptible to CSDS also have a decrease in VTA DA soma size. Our current objective is to identify the molecular mechanisms underlying these morphological changes. Given our data that morphine‐induced changes in VTA DA soma size are TORC2‐dependent and recent evidence that TORC2 signaling modulates cytoskeletal remodeling in the hippocampus, we hypothesize morphine and stress may alter the actin cytoskeleton in VTA DA neurons through alteration of TORC2 activity. We completed western blot analyses on micro‐dissected VTA tissue from mice exposed to chronic morphine or CSDS and found a significant decrease in the phosphorylation of cofilin, a protein involved in severing actin filaments. We are now examining molecules upstream of cofilin, such as Rac1 and p‐21 activated kinase (PAK) to determine if exposure to chronic morphine or stress similarly alters activity of these proteins. Additionally, to further investigate the potential role of TORC2 on mediating changes in the actin cytoskeleton, we are performing western blot analysis using VTA tissue from mice that either overexpress or knockout Rictor, a critical component of TORC2. Overall, our goal is to determine the molecular mechanisms underlying changes in VTA structural plasticity in the hopes of identifying novel targets for therapeutic intervention in addiction and depression. Support or Funding Information PhRMA Foundation Pre‐Doctoral Fellowship in Pharmacology/Toxicology (SK) Integrative Pharmacological Sciences Training Program: T32 GM092715 (SK) NIDA: R01 DA039895‐01A1 (MMR) NIDA: R03 DA037426 (MMR) PhRMA Foundation Research Starter Grant (MMR)