Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6

Bruce Ladenheim, Irina N. Krasnova, Xiaolin Deng, Jonathan M. Oyler, Aldo Polettini, Timothy H. Moran, Marilyn A. Huestis, Jean Lud Cadet

Research output: Contribution to journalShort surveypeer-review

103 Scopus citations


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 caudateputamen (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.

Original languageEnglish (US)
Pages (from-to)1247-1256
Number of pages10
JournalMolecular Pharmacology
Issue number6
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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