Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 9, Pages 2212-2225Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4847-03.2004
Keywords
addiction; reward; accumbens; gene expression; TNF; neuroprotection
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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 mug) 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 mug) 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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