Calcineurin/NFAT-Induced Up-Regulation of the Fas Ligand/Fas Death Pathway Is Involved in Methamphetamine-Induced Neuronal Apoptosis
Methamphetamine [METH ("speed")] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 3; pp. 868 - 873 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
18.01.2005
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | Methamphetamine [METH ("speed")] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METH-treated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL- and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 S.J. and X.D. contributed equally to this work. Author contributions: J.L.C. designed research; S.J., X.D., B.L., M.T.M., A.C., and N.-s.C. performed research; S.J., X.D., B.L., A.C., and M.T.M. analyzed data; and S.J., X.D., and J.L.C. wrote the paper. Edited by Tomas Hökfelt, Karolinska Institutet, Stockholm, Sweden, and approved December 9, 2004 This paper was submitted directly (Track II) to the PNAS office. Abbreviations: METH, methamphetamine; DA, dopamine; TF, transcription factor; FasL, Fas ligand; ENK, enkephalin; NFAT, nuclear factor of activated T cells; SP, Substance P; GAD, glutamic acid decarboxylase; Egr, early growth response gene. To whom correspondence should be addressed. E-mail: jcadet@intra.nida.nih.gov. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0404990102 |