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The Journal of Neuroscience, July 1, 1998, 18(13):4861-4869
Role of Dopamine Transporter in Methamphetamine-Induced
Neurotoxicity: Evidence from Mice Lacking the Transporter
Fabio
Fumagalli,
Raul R.
Gainetdinov,
Kenneth J.
Valenzano, and
Marc G.
Caron
Howard Hughes Medical Institute Laboratories, Department of Cell
Biology and Medicine, Duke University Medical Center, Durham, North
Carolina 27710
The role of the dopamine transporter (DAT) in mediating the
neurotoxic effects of methamphetamine (METH) was tested in mice lacking
DAT. Dopamine (DA) and serotonin (5-HT) content, glial fibrillary
acidic protein (GFAP) expression, and free radical formation were
assessed as markers of METH neurotoxicity in the striatum and/or
hippocampus of wild-type, heterozygote, and homozygote (DAT  /)
mice. Four injections of METH (15 mg/kg, s.c.), each given 2 hr apart,
produced 80 and 30% decreases in striatal DA and 5-HT levels,
respectively, in wild-type animals 2 d after administration. In
addition, GFAP mRNA and protein expression levels, extracellular DA
levels, and free radical formation were increased markedly. Hippocampal
5-HT content was decreased significantly as well (43%). Conversely, no
significant changes were observed in total DA content, GFAP expression,
extracellular DA levels, or free radical formation in the striatum of
DAT / mice after METH administration. However, modest decreases
were observed in striatal and hippocampal 5-HT levels (10 and 17%,
respectively). These observations demonstrate that DAT is required for,
and DA is an essential mediator of, METH-induced striatal dopaminergic neurotoxicity, whereas serotonergic deficits are only partially dependent on DAT.
Key words:
dopamine transporter; methamphetamine; microdialysis; serotonin; free radical; GFAP
Copyright © 1998 Society for Neuroscience 0270-6474/98/18134861-09$05.00/0
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