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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Abstract

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
Volume24
Issue number9
DOIs
Publication statusPublished - 03-03-2004

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Methamphetamine
Substance-Related Disorders
Tumor Necrosis Factor-alpha
Dopamine
Corpus Striatum
Dopamine Plasma Membrane Transport Proteins
Synaptosomes
Dopaminergic Neurons
Inbred C57BL Mouse

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Nakajima, Akira ; Yamada, Kiyofumi ; Nagai, Taku ; Uchiyama, Takehisa ; Miyamoto, Yoshiaki ; Mamiya, Takayoshi ; He, Jue ; Nitta, Atsumi ; Mizuno, Makoto ; Tran, Manh Hung ; Seto, Aika ; Yoshimura, Masako ; Kitaichi, Kiyoyuki ; Hasegawa, Takaaki ; Saito, Kuniaki ; Yamada, Yasuhiro ; Seishima, Mitsuru ; Sekikawa, Kenji ; Kim, Hyoung Chun ; Nabeshima, Toshitaka. / Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 9. pp. 2212-2225.
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abstract = "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.",
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Nakajima, A, Yamada, K, Nagai, T, Uchiyama, T, Miyamoto, Y, Mamiya, T, He, J, Nitta, A, Mizuno, M, Tran, MH, Seto, A, Yoshimura, M, Kitaichi, K, Hasegawa, T, Saito, K, Yamada, Y, Seishima, M, Sekikawa, K, Kim, HC & Nabeshima, T 2004, 'Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity', Journal of Neuroscience, vol. 24, no. 9, pp. 2212-2225. https://doi.org/10.1523/JNEUROSCI.4847-03.2004

Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity. / Nakajima, Akira; Yamada, Kiyofumi; Nagai, Taku; Uchiyama, Takehisa; Miyamoto, Yoshiaki; Mamiya, Takayoshi; He, Jue; Nitta, Atsumi; Mizuno, Makoto; Tran, Manh Hung; Seto, Aika; Yoshimura, Masako; Kitaichi, Kiyoyuki; Hasegawa, Takaaki; Saito, Kuniaki; Yamada, Yasuhiro; Seishima, Mitsuru; Sekikawa, Kenji; Kim, Hyoung Chun; Nabeshima, Toshitaka.

In: Journal of Neuroscience, Vol. 24, No. 9, 03.03.2004, p. 2212-2225.

Research output: Contribution to journalArticle

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T1 - Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity

AU - Nakajima, Akira

AU - Yamada, Kiyofumi

AU - Nagai, Taku

AU - Uchiyama, Takehisa

AU - Miyamoto, Yoshiaki

AU - Mamiya, Takayoshi

AU - He, Jue

AU - Nitta, Atsumi

AU - Mizuno, Makoto

AU - Tran, Manh Hung

AU - Seto, Aika

AU - Yoshimura, Masako

AU - Kitaichi, Kiyoyuki

AU - Hasegawa, Takaaki

AU - Saito, Kuniaki

AU - Yamada, Yasuhiro

AU - Seishima, Mitsuru

AU - Sekikawa, Kenji

AU - Kim, Hyoung Chun

AU - Nabeshima, Toshitaka

PY - 2004/3/3

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