ROLE OF DOPAMINE TRANSPORTER IN METHAMPHETAMINE-INDUCED NEUROTOXICITY- EVIDENCE FROM MICE LACKING THE TRANSPORTER

The role of the dopamine transporter (DAT) in mediating the neurotoxic effects of methamphetamine (METH) was tested in mice lacking DAT. Dop amine (DA) and serotonin (5-HT) content, glial fibrillary acidic prote in (GFAP) expression, and free radical formation were assessed as mark ers of METH neurotoxicity in the striatum and/or hippocampus of wild-t ype, heterozygote, and homozygote (DAT -/-) mice. Four injections of M ETH (15 mg/kg, s.c.), each given 2 hr apart, produced 80 and 30% decre ases in striatal DA and 5-HT levels, respectively, in wildtype animals 2 d after administration. In addition, GFAP mRNA and protein expressi on levels, extracellular DA levels, and free radical formation were in creased markedly. Hippocampal 5-HT content was decreased significantly as well (43%). Conversely, no significant changes were observed in to tal DA content, GFAP expression, extracellular DA levels, or free radi cal formation in the striatum of DAT -/- mice after METH administratio n. However, modest decreases were observed in striatal and hippocampal 5-HT levels (10 and 17%, respectively). These observations demonstrat e that DAT is required for, and DA is an essential mediator of, METH-i nduced striatal dopaminergic neurotoxicity, whereas serotonergic defic its are only partially dependent on DAT.