Methamphetamine-Induced Neurotoxicity Is Attenuated in Transgenic Mice with a Null Mutation for Interleukin-6
- Bruce Ladenheim1,
- Irina N. Krasnova1,
- Xiaolin Deng1,
- Jonathan M. Oyler2,
- Aldo Polettini2,
- Timothy H. Moran3,
- Marilyn A. Huestis2 and
- Jean Lud Cadet1
- 1Molecular Neuropsychiatry Section (B.L., I.N.K., X.D., J.L.C.) and2Chemistry and Drug Metabolism Section (J.M.O., A.P., M.A.H.), National Institutes of Health/National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland; and 3Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (T.H.M.)
Abstract
Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6−/−) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [125I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6−/− animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6−/− animals. Moreover, METH induced decreases in [125I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6−/− mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [3H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6−/− animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6−/− mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.
Footnotes
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Send reprint requests to: Jean Lud Cadet, M.D., Molecular Neuropsychiatry Section, NIH/NIDA Intramural Research program, 5500 Nathan Shock Drive, Baltimore, MD. E-mail:jcadet{at}intra.nida.nih.gov
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This work was partially supported by National Institutes of Health Grant HD 24605 (T.H.M.).
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B.L. and I.N.K. have contributed equally to this work.
- Abbreviations:
- METH
- methamphetamine
- DAT
- dopamine transporters
- DA
- dopamine
- NO
- nitric oxide
- IL-6
- interleukin-6
- CNS
- central nervous system
- IL-6+/+
- wild-type mice
- IL-6−/−
- interleukin-6 knockout mice
- CPu
- caudate-putamen
- NE
- norepinephrine
- DOPAC
- 3,4-dihydroxyphenyl acetic acid
- 5-HIAA
- 5-hydroxyindoleacetic acid
- SERT
- serotonin transporters
- MBBS
- mitochondrial benzodiazepine binding sites
- TUNEL
- terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled/labeling
- GC
- gas chromatography
- MS
- mass spectrometry
- AMPH
- amphetamine
- IL-1β
- interleukin-1β
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- Received March 13, 2000.
- Accepted August 30, 2000.
- U.S. Government
