Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.
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.
Ladenheim
B
B
Molecular Neuropsychiatry Section, National Institutes of Health/National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, USA.
Krasnova
I N
IN
Deng
X
X
Oyler
J M
JM
Polettini
A
A
Moran
T H
TH
Huestis
M A
MA
Cadet
J L
JL
D000661:Amphetamine / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D015259:Dopamine Agents / Q000493:pharmacokinetics / Q000633:toxicity; D050483:Dopamine Plasma Membrane Transport Proteins; D004347:Drug Interactions; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins; D020258:Neurotoxicity Syndromes; D050486:Serotonin Plasma Membrane Transport Proteins; D013696:Temperature
D002352:Carrier Proteins; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D001569:Benzodiazepines; D008694:Methamphetamine; D000661:Amphetamine