Methamphetamine-induced neurotoxicity is associated with increased striatal AP-1 DNA-binding activity in mice

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 x 2 group, but were still significantly decreased in the METH x 3 and x 4 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 x 2 and x 3 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 x 4 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.