TY - JOUR T1 - Role of Tumor Necrosis Factor-α in Methamphetamine-Induced Drug Dependence and Neurotoxicity JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2212 LP - 2225 DO - 10.1523/JNEUROSCI.4847-03.2004 VL - 24 IS - 9 AU - Akira Nakajima AU - Kiyofumi Yamada AU - Taku Nagai AU - Takehisa Uchiyama AU - Yoshiaki Miyamoto AU - Takayoshi Mamiya AU - Jue He AU - Atsumi Nitta AU - Makoto Mizuno AU - Manh Hung Tran AU - Aika Seto AU - Masako Yoshimura AU - Kiyoyuki Kitaichi AU - Takaaki Hasegawa AU - Kuniaki Saito AU - Yasuhiro Yamada AU - Mitsuru Seishima AU - Kenji Sekikawa AU - Hyoung-Chun Kim AU - Toshitaka Nabeshima Y1 - 2004/03/03 UR - http://www.jneurosci.org/content/24/9/2212.abstract N2 - 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. ER -