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

1996, Molecular Brain Research

Multiple injections of methamphetamine WETHI produce long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system. The drug also causes increases in AP-1 A-binding activity in mice. Im the present study. wc tested the idea that toxic doses of METH might cause long-term increases in AP-I NA-binding. ice were giveq 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 activitj almost returned back to control level in the X 2 and X 3 injection groups at the 23. h and 1 week time point, but there were still increased levels of AP-l-binding activity in the METH X4 group. These findings raise the possibility that METH-induced neurotoxicity might involve prolonged activation of AP-I transcription factor. This might be related to the report that c-jijs or c-jm acti\.ation n-q be important in some models of neurodegeneration. Although methamphetamine (METH) is a well known toxicant, the cellular and molecular mechanisms involved in causing damage to monoaminergic systems are not fully clear. We have shown that oxygen-based radicals are probably involved in METH-induced neurotoxicity to DA systems [f-3,5,6]. Studies from this laboratory have also shown that the AP-1 DNA binding activity can be induced by methamphetamine administration in a dose-dependent fashion [ 121. In that study, non-toxic doses of the drug were used. AP-1 (.Tun/Fos) is constitutivefy expressed at low fevels in usual situations but can be rapidly induced in situations such as brain injury, seizure activity, stress and drug treatment [2,7,9.17]. In addition, Jun (AP-1) is also activated by carcinogenic agents, UV, gamma irradiation, NO, and DNA damage [S, 10,l I, 151. Because oxygen-based radicals are known activators of AP-1 [ 12,151 and because ??