Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity.
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.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Akira
A
Nakajima
Kiyofumi
K
Yamada
Taku
T
Nagai
Takehisa
T
Uchiyama
Yoshiaki
Y
Miyamoto
Takayoshi
T
Mamiya
Jue
J
He
Atsumi
A
Nitta
Makoto
M
Mizuno
Manh Hung
MH
Tran
Aika
A
Seto
Masako
M
Yoshimura
Kiyoyuki
K
Kitaichi
Takaaki
T
Hasegawa
Kuniaki
K
Saito
Yasuhiro
Y
Yamada
Mitsuru
M
Seishima
Kenji
K
Sekikawa
Hyoung-Chun
HC
Kim
Toshitaka
T
Nabeshima
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D019966:Substance-Related Disorders / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D015703:Antigens, CD; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D008694:Methamphetamine; D004298:Dopamine