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Research ArticleArticle

AC927, a σ Receptor Ligand, Blocks Methamphetamine-Induced Release of Dopamine and Generation of Reactive Oxygen Species in NG108-15 Cells

Nidhi Kaushal, Meenal Elliott, Matthew J. Robson, Anand Krishnan V. Iyer, Yon Rojanasakul, Andrew Coop and Rae R. Matsumoto
Molecular Pharmacology March 2012, 81 (3) 299-308; DOI: https://doi.org/10.1124/mol.111.074120
Nidhi Kaushal
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Meenal Elliott
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Matthew J. Robson
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Anand Krishnan V. Iyer
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Yon Rojanasakul
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Andrew Coop
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Rae R. Matsumoto
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Abstract

Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity with high or repeated dosing. Earlier studies demonstrated the ability of the selective σ receptor ligand N-phenethylpiperidine oxalate (AC927) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. With the use of differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators such as apoptosis, necrosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation, which was detected with the fluorigenic substrate 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescin diacetate, acetyl ester, in a concentration- and time-dependent manner. N-Acetylcysteine, catalase, and l-NG-monomethyl arginine citrate inhibited the ROS/RNS fluorescence signal induced by methamphetamine, which suggests the formation of hydrogen peroxide and RNS. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation, and dopamine release in NG108-15 cells. Together, the data suggest that modulation of σ receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA 013978].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.074120.

  • ABBREVIATIONS:

    AC927
    N-phenethylpiperidine oxalate
    ANOVA
    analysis of variance
    CM-H2DCFDA
    5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescin diacetate, acetyl ester
    DAT
    dopamine transporter
    DMEM
    Dulbecco's modified Eagle's medium
    DMSO
    dimethylsulfoxide
    ER
    endoplasmic reticulum
    FBS
    fetal bovine serum
    HAT
    hypoxanthine-aminopterin-thymidine
    METH
    methamphetamine
    NAC
    N-acetylcysteine
    l- NMMA
    l- NG-monomethyl arginine citrate
    MFI
    mean fluorescence intensity
    NET
    norepinephrine transporter
    NO
    nitric oxide
    NOS
    nitric-oxide synthase
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    RNS
    reactive nitrogen species
    ROS
    reactive oxygen species
    SERT
    serotonin transporter
    TEMED
    N,N,N′,N′-tetramethylethylenediamine
    TH
    tyrosine hydroxylase.

  • Received June 17, 2011.
  • Accepted November 18, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

AC927 Blocks METH-Induced Neurotoxicity in NG108-15 Cells

Nidhi Kaushal, Meenal Elliott, Matthew J. Robson, Anand Krishnan V. Iyer, Yon Rojanasakul, Andrew Coop and Rae R. Matsumoto
Molecular Pharmacology March 1, 2012, 81 (3) 299-308; DOI: https://doi.org/10.1124/mol.111.074120

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Research ArticleArticle

AC927 Blocks METH-Induced Neurotoxicity in NG108-15 Cells

Nidhi Kaushal, Meenal Elliott, Matthew J. Robson, Anand Krishnan V. Iyer, Yon Rojanasakul, Andrew Coop and Rae R. Matsumoto
Molecular Pharmacology March 1, 2012, 81 (3) 299-308; DOI: https://doi.org/10.1124/mol.111.074120
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