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The Journal of Neuroscience, March 3, 2004, 24(9):2212-2225; doi:10.1523/JNEUROSCI.4847-03.2004

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Behavioral/Systems/Cognitive
Role of Tumor Necrosis Factor- in Methamphetamine-Induced Drug Dependence and Neurotoxicity

Akira Nakajima,^1 * Kiyofumi Yamada,^1,2 * Taku Nagai,¹ Takehisa Uchiyama,¹ Yoshiaki Miyamoto,¹ Takayoshi Mamiya,¹ Jue He,¹ Atsumi Nitta,¹ Makoto Mizuno,¹ Manh Hung Tran,¹ Aika Seto,¹ Masako Yoshimura,¹ Kiyoyuki Kitaichi,³ Takaaki Hasegawa,³ Kuniaki Saito,⁴ Yasuhiro Yamada,⁴ Mitsuru Seishima,⁴ Kenji Sekikawa,⁵ Hyoung-Chun Kim,⁶ and Toshitaka Nabeshima¹

¹Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan, ²Laboratory of Neuropsychopharmacology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934, Japan, ³Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan, ⁴Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan, ⁵Department of Immunology, National Institute of Animal Health, Tsukuba 305-0856, Japan, and ⁶Neurotoxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea

Tumor necrosis factor- (TNF-), 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- in METH-induced dependence and neurotoxicity. Repeated treatment with METH (2 mg/kg for 5 d) in rats induced a significant increase in TNF- mRNA and protein expression in the brain. Exogenous TNF- (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- in behavioral and neurochemical effects of METH, we used mice with targeted deletions of the TNF- gene. TNF--(-/-) 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- in METH-induced dopamine (DA) release and uptake in vitro and in vivo in C57BL/6 mice. Exogenous TNF- (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- activated vesicular DA uptake by itself and diminished the METH-induced decrease in vesicular DA uptake. Our findings suggest that TNF- 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.

Key words: addiction; reward; accumbens; gene expression; TNF; neuroprotection

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Received Aug 1, 2003; revised January 17, 2004; accepted January 18, 2004.

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