Cited by 176Neurotransmitter Receptor Influence on BehaviorTryptophan and brain disordersNeuroinflammation and Neurodegeneration Mechanisms

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

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Nakajima, Akira, Yamada, Kiyofumi, Nagai, Taku, Uchiyama, Takehisa, Miyamoto, Yoshiaki, Mamiya, Takayoshi, He, Jue, Nitta, Atsumi +12 more·2004·The Journal of Neuroscience

Abstract

Tumor necrosis factor-alpha (TNF-alpha), 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-alpha in METH-induced dependence and neurotoxicity. Repeated treatment with METH (2 mg/kg for 5 d) in rats induced a significant increase in TNF-alpha mRNA and protein expression in the brain. Exogenous TNF-alpha (1-4 microg) 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-alpha in behavioral and neurochemical effects of METH, we used mice with targeted deletions of the TNF-alpha gene. TNF-alpha-(-/-) 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-alpha in METH-induced dopamine (DA) release and uptake in vitro and in vivo in C57BL/6 mice. Exogenous TNF-alpha (4 microg) 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-alpha activated vesicular DA uptake by itself and diminished the METH-induced decrease in vesicular DA uptake. Our findings suggest that TNF-alpha 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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Authors
Nakajima, A., Yamada, K., Nagai, T., Uchiyama, T., Miyamoto, Y., Mamiya, T., He, J., Nitta, A., Mizuno, M., Tran, M. H., Seto, A., Yoshimura, M., Kitaichi, K., Hasegawa, T., Saito, K., Yamada, Y., Seishima, M., Sekikawa, K., Kim, H.-C., & Nabeshima, T.
Affiliations
  • Nagoya University Hospital (JP)
  • Kanazawa University (JP)
  • Nagoya University (JP)
  • Gifu University (JP)
  • National Institute of Animal Health (JP)
  • Kangwon National University (KR)
Venue
The Journal of Neuroscience
Published
2004-03-03
Volume
24
Issue
9
Pages
2212-2225
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2130014240
Cited by
176
References
97
Citations by year
2026: 5 · 2025: 8 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 12 · 2016: 7 · 2015: 7 · 2014: 15 · 2013: 7 · 2012: 8
FWCI
4.22
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Novartis Foundation
  • Ministry of Health, Labour and Welfare
  • NOVARTIS Foundation (Japan) for the Promotion of Science
  • Japan Society for the Promotion of Science
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
TNF-α, methamphetamine, drug addiction, dopaminergic neurotoxicity, locomotor sensitization, drug reward, dopamine release, dopamine uptake, striatum, TNF-alpha knockout mice, neuroprotection, inflammatory cytokines
MeSH terms
Animals, Corpus Striatum, Discrimination Learning, Disease Models, Animal, Dopamine, Male, Methamphetamine, Mice, Inbred C57BL, Microinjections, Motor Activity, Nucleus Accumbens, Reward, RNA, Messenger, Spatial Behavior, Tumor Necrosis Factor-alpha, Antigens, CD, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Rats, Wistar, Microdialysis, Receptors, Tumor Necrosis Factor, Mice, Knockout, Substance-Related Disorders, Neurotoxicity Syndromes, Receptors, Tumor Necrosis Factor, Type I, Mice, Rats

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