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

Mol Pharmacol. 2000 Dec;58(6):1247-56. doi: 10.1124/mol.58.6.1247.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Interleukin-6 / metabolism*
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins*
  • Methamphetamine / pharmacokinetics
  • Methamphetamine / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mutation
  • Nerve Tissue Proteins*
  • Neurotoxicity Syndromes
  • Serotonin Plasma Membrane Transport Proteins
  • Temperature

Substances

  • Carrier Proteins
  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Interleukin-6
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Benzodiazepines
  • Methamphetamine
  • Amphetamine