METHAMPHETAMINE-INDUCED NEUROTOXICITY IS ASSOCIATED WITH INCREASED STRIATAL AP-1 DNA-BINDING ACTIVITY IN MICE

Multiple injections of methamphetamine (METH) produce long-lasting neu rotoxic effects on the nigrostriatal dopamine (DA) system. The drug al so causes increases in AP-1 DNA-binding activity in mice. In the prese nt 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 ma rkedly 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, bu t were still significantly decreased in the METH X3 and X4 groups. Sim ilar drug administration schedules caused increases in AP-1 DNA-bindin g activity at the 3 h time point in all groups. The AP-l-binding activ ity almost returned back to control level in the X2 and X3 injection g roups at the 24 h and 1 week time point, but there were still increase d levels of AP-1-binding activity in the METH X4 group. These findings raise the possibility that METH-induced neurotoxicity might involve p rolonged activation of AP-1 transcription factor. This might be relate d to the report that c-fos or c-jun activation may be important in som e models of neurodegeneration.