Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity
Open accessAbstract
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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Repeated methamphetamine treatment increases TNFα throughout the brain.
“repeated Meth treatment increased TNFα throughout the brain (Nakajima et al., 2004)”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Nakajima et al., 2004
Pretreatment with exogenous TNFα reduces methamphetamine-induced locomotor activity, the rewarding effects of methamphetamine, and several indicators of neurotoxicity.
“pretreatment with exogenous TNFα reduced Meth-induced locomotor activity, the rewarding effects of Meth, and several indicators of neurotoxicity.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Nakajima et al., 2004
Methamphetamine-induced behavioral hyperactivity and sensitization is potentiated in TNFα knockout animals.
“Meth-induced behavioral hyperactivity and sensitization was potentiated in TNFα KO animals.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Nakajima et al., 2004
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Depression and type 2 diabetes: Inflammatory mechanisms of a psychoneuroendocrine co-morbidity
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“Consistent with several studies cited above, repeated Meth treatment in- creased TNFa throughout the brain (Nakajima et al., 2004).”
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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)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-03-03
- Volume
- 24
- Issue
- 9
- Pages
- 2212-2225
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730419
- 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
- hybrid
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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