501. Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.
- Author
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Ladenheim B, Krasnova IN, Deng X, Oyler JM, Polettini A, Moran TH, Huestis MA, and Cadet JL
- Subjects
- Amphetamine pharmacokinetics, Amphetamine toxicity, Animals, Benzodiazepines pharmacology, Carrier Proteins metabolism, Chromatography, High Pressure Liquid, Dopamine Agents pharmacokinetics, Dopamine Agents toxicity, Dopamine Plasma Membrane Transport Proteins, Drug Interactions, In Situ Nick-End Labeling, Interleukin-6 genetics, Membrane Glycoproteins metabolism, Methamphetamine pharmacokinetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mitochondria drug effects, Mitochondria metabolism, Mutation, Neurotoxicity Syndromes, Serotonin Plasma Membrane Transport Proteins, Temperature, Interleukin-6 metabolism, Membrane Transport Proteins, Methamphetamine toxicity, Nerve Tissue Proteins
- 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 [(125)I]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 [(125)I]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 [(3)H]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.
- Published
- 2000
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