The effects of low-dose methamphetamine pretreatment on endoplasmic reticulum stress and methamphetamine neurotoxicity in the rat midbrain

Methamphetamine (METH) neurotoxicity is involved in METH-related deaths. It has been suggested that the midbrain, together with the striatum, is affected by METH neurotoxicity and the endoplasmic reticulum (ER) stress is induced in the processes of METH neurotoxicity. In this study, we examined the effects of low-dose METH administration for 5 d on GRP78 and C/EBP homologous protein (CHOP), both of which are induced under ER stress, and METH neurotoxicity in the rat midbrain. We showed that 1 mg/kg of METH induced an increase in GRP78 protein and mRNA expression 1 d after the last injection, but had no effect on the levels of CHOP, tyrosine hydroxylase (TH), or GFAP. Secondly, we evaluated the induction of ER stress and the extent of METH neurotoxicity in the midbrain of animals pretreated with METH. In animals pretreated with saline, we observed elevated CHOP levels, together with decreased TH levels and increased GFAP levels, indicative of METH neurotoxicity, after neurotoxic METH administration, while there was no significant change in GRP78 levels. In contrast, low-dose METH (1.0 mg/kg) pretreatment increased GRP78 levels and inhibited the induction of CHOP in the midbrain without METH neurotoxicity. These findings of ER stress in animals pretreated with METH were associated with an early increase in SOD1 levels and upregulation of Bcl-2. Therefore, our study suggests that pretreatment with low-dose METH may be protective against METH neurotoxicity in the midbrain, leading to the suppression of oxidative stress and apoptotic mechanisms, in part via ER stress-related pathways. Because chronic human METH abusers administrate low-dose METH repeatedly over an extended period before lethal injection, investigation of the pathophysiology of METH neurotoxicity in animals pretreated with low-dose METH might provide useful information on the pathophysiology of chronic and/or lethal METH use in cases of METH-related deaths.