Methamphetamine Induces Dopamine D1 Receptor-Dependent Endoplasmic Reticulum Stress-Related Molecular Events in the Rat Striatum

Abstract

Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain.

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

“…As previously reported, MA is known to induce the expressions of several of ER-stress molecules in various regions of rat brains [28, 54]. Our findings are consistent with these prior reports in that we observed increase in various ER stress proteins in different brain regions of mice.…”

“…As shown in Figure 4A, MA treatment increased the expressions of phospho PERK, and phospho eIF2α. In addition, earlier reports have demonstrated increase in ATF4 in rat striatum due to MA treatment [28]. Since ATF4 activation is downstream of PERK pathway, we measured the levels of ATF4.…”

“…It has been implicated in several diseases such as Parkinson's disease, ischemia, atherosclerosis and diabetes [23–25]. In addition, increased ER stress has been correlated with MA-mediated neurotoxicity [13, 26–28]. Several reports have demonstrated increased expressions of various ER stress markers and chaperones due to MA leading to neuronal death.…”

Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum

“…Indeed, HDAC6 provides an important link between autophagy and the unfolded protein response (UPR) (Pandey et al, 2007). These observations are of interest because toxic doses of METH cause significant changes in the expression of proteins involved in the UPR (Beauvais et al, 2011; Jayanthi et al, 2004; Jayanthi et al, 2009) and suggest that METH-induced decreased HDAC6 expression might serve to increase acetylation of some chaperone proteins (Bali et al, 2005). The other class IIB member, HDAC10, was identified in 2002 (Guardiola and Yao, 2002; Kao et al, 2002; Tong et al, 2002).…”

Repeated Exposure to D-Amphetamine Decreases Global Protein Synthesis and Regulates the Translation of a Subset of mRNAs in the Striatum

“…While GADD34 comprises a negative feedback loop to reverse the translational attenuation mediated by the enhanced eIF2α phosphorylation, the transcription factor CHOP promotes the expression of genes involved in apoptosis (Wang et al, 1998; Zinszner et al, 1998; Novoa et al, 2001). Previous experiments performed in rats indicate that repeated exposure to psychostimulants, including cocaine, D -amphetamine, or methamphetamine, activates the ER stress response, which through the engagement of apoptotic pathways leads to striatal neurotoxicity (Jayanthi et al, 2004, 2009; Krasnova et al, 2005; Beauvais et al, 2011; Go et al, 2016). Our results clearly highlight that the effects induced by repeated exposure to D -amphetamine are radically different in mice.…”