Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity

Akira Nakajima, Kiyofumi Yamada, Taku Nagai, Takehisa Uchiyama, Yoshiaki Miyamoto, Takayoshi Mamiya, Jue He, Atsumi Nitta, Makoto Mizuno, Manh Hung Tran, Aika Seto, Masako Yoshimura, Kiyoyuki Kitaichi, Takaaki Hasegawa, Kuniaki Saito, Yasuhiro Yamada, Mitsuru Seishima, Kenji Sekikawa, Hyoung Chun Kim, Toshitaka Nabeshima

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149 Citations (Scopus)


Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is now emerging as an important modulator of the function of the CNS. Methamphetamine (METH) is a widely abused psychostimulant that causes euphoria, hyperactivity, and drug dependence. High doses of METH cause long-term neurotoxicity in dopaminergic neurons. In this study, we investigated a role of TNF-α in METH-induced dependence and neurotoxicity. Repeated treatment with METH (2 mg/kg for 5 d) in rats induced a significant increase in TNF-α mRNA and protein expression in the brain. Exogenous TNF-α (1-4 μg) blocked locomotor-stimulating and rewarding effects of METH, as well as METH (4 mg/kg; four times at 2 hr intervals)-induced dopaminergic neurotoxicity in mice. To examine a role of endogenous TNF-α in behavioral and neurochemical effects of METH, we used mice with targeted deletions of the TNF-α gene. TNF-α-(-/-) mice showed enhanced responses to the locomotor-sensitizing, rewarding, and neurotoxic effects of METH compared with wild-type mice. We also examined the role of TNF-α in METH-induced dopamine (DA) release and uptake in vitro and in vivo in C57BL/6 mice. Exogenous TNF-α (4 μg) attenuated the METH-induced increase in extracellular striatal DA in vivo and potentiated striatal DA uptake into synaptosomes in vitro and in vivo. Furthermore, TNF-α activated vesicular DA uptake by itself and diminished the METH-induced decrease in vesicular DA uptake. Our findings suggest that TNF-α plays a neuroprotective role in METH-induced drug dependence and neurotoxicity by activating plasmalemmal and vesicular DA transporter as well as inhibiting METH-induced increase in extracellular DA levels.

Original languageEnglish
Pages (from-to)2212-2225
Number of pages14
JournalJournal of Neuroscience
Issue number9
Publication statusPublished - 03-03-2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)


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