Multiple injections of methamphetamine (METH) produce long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system. The drug also causes increases in AP-1 DNA-binding activity in mice. In the present study, we tested the idea that toxic doses of METH might cause long-term increases in AP-1 DNA-binding. Mice were given 10 mg/kg of METH 2, 3 or 4 times at a 2 h interval in 1 day. Striatal DA levels were markedly decreased at 3 h and 24 h in all injection groups. After 1 week, striatal DA level recovered to near control in the METH x2 group, but were still significantly decreased in the METH x3 and x4 groups. Similar drug administration schedules caused increases in AP-1 DNA-binding activity at the 3 h time point in all groups. The AP-1-binding activity almost returned back to control level in the x2 and x3 injection groups at the 24 h and 1 week time point, but there were still increased levels of AP-1-binding activity in the METH x4 group. These findings raise the possibility that METH-induced neurotoxicity might involve prolonged activation of AP-1 transcription factor. This might be related to the report that c-fos or c-jun activation may be important in some models of neurodegeneration.