Vol. 58, Issue 6, 1247-1256, December 2000

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, and Jean Lud Cadet

Molecular Neuropsychiatry Section (B.L., I.N.K., X.D., J.L.C.) and Chemistry 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 Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (T.H.M.)

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.