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Molecular Mechanisms of Methamphetamine-Induced Neurotoxicity: Insights Obtained Through cDNA Array Analyses

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Abstract:

Methamphetamine (METH) is an abused psychostimulant that can cause psychotic symptoms, cognitive and psychomotor deficits, stroke, and death. METH‐induced neurotoxicity includes neural cell death which occurs via processes that resemble apoptosis. We have used cDNA array technology to investigate transcriptional responses that occur in the rodent brain after a toxic dose of the drug. These studies showed that the drug can cause an early pattern of gene induction which is characterized by changes in transcription factors. A more delayed response included changes in the expression of genes involved in DNA repair, regulation of trophic factors, and in cell death pathways. Interestingly, regulation of some of these transcription factors has been shown to be involved in controlling the expression of Fas ligand (FasL) which can trigger apoptosis in a number of models of cell death. Thus, these results indicate that METH can cause some of its degenerative effects, in part, via activation of a receptor‐mediated cell death pathway consequent to multiple transcription factor‐mediated FasL up‐regulation. When taken together, these observations indicate that METH‐induced toxicity results from the balance of pro‐death/protective mechanisms in the rodent brain.

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Abbreviations

AICD:

activity-induced cell death

AP-1:

activator protein-1

AP-site:

apurinic/apyrimidinic site

BER:

base excision repair

DA:

dopamine

DAT:

dopamine transporter

FGF:

fibroblast growth factor

IGF:

insulin growth factor

MMR:

mismatch repair

NER:

nucleotide excision repair

OGG1:

8-oxo-guanine glycosylase-1

ROS:

reactive oxygen species

TGF:

transforming growth factor

TH:

tyrosine hydroxylase

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Authors
  1. S. Jayanthi
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  2. M. T. McCoy
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  3. J. L. Cadet
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Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, New York, 10962, Orangeburg, USA

    Abel Lajtha (Director) (Director)

  2. Technion‐Rappaport Family Faculty of Medicine, Efron St., POBox 9697, 31096, Haifa, Israel

    Moussa B. H. Youdim (Professor of Pharmacology Professor of Life Sciences Director of Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research) (Professor of Pharmacology Professor of Life Sciences Director of Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research)

  3. Clinic and Policlinic of Psychiatry and Psychotherapy Dept. Clinical Neurochemistry, University of Würzburg, Füchsleinstr. 15, 97080, Würzburg, Germany

    Peter Riederer

  4. Eve Topf Center for Neurodegenerative Diseases Research and Dept. of Pharmacology, Faculty of Medicine Technion, Efron St., P.O.B. 9697, 31096, Haifa, Israel

    Sylvia A. Mandel

  5. Department of Neurosciences, University of Padova Medical School, Via Giustiniani 5, 35128, Padova, Italy

    Leontino Battistin

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Jayanthi, S., McCoy, M.T., Cadet, J.L. (2007). Molecular Mechanisms of Methamphetamine-Induced Neurotoxicity: Insights Obtained Through cDNA Array Analyses. In: Lajtha, A., Youdim, M.B.H., Riederer, P., Mandel, S.A., Battistin, L. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York, NY. https://doi.org/10.1007/978-0-387-30377-2_10

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