Abstract
Methamphetamine (METH) abuse is known to cause executive dysfunction. However, the molecular mechanism underlying METH induced executive dysfunction remains unclear. Go/NoGo experiment was performed in mice to evaluate METH-induced executive dysfunction. Immunoblot analysis of Nuclear factor-E2-related factor 2 (Nrf2), phosphorylated Nrf2 (p-Nrf2), heme-oxygenase-1 (HO-1), Glucose Regulated Protein 78(GRP78), C/EBP homologous protein (CHOP), Bcl-2, Bax and Caspase3 was performed to evaluate the levels of oxidative stress, endoplasmic reticulum (ER) stress and apoptosis in the dorsal striatum (Dstr). Malondialdehyde (MDA) levels and glutathione peroxidase (GSH-Px) activity was conducted to evaluate the level of oxidative stress. TUNEL staining was conducted to detect apoptotic neurons. The animal Go/NoGo testing confirmed that METH abuse impaired the inhibitory control ability of executive function. Meanwhile, METH down-regulated the expression of p-Nrf2, HO-1 and GSH-Px and activated ER stress and apoptosis in the Dstr. Microinjection of Tert-butylhydroxyquinone (TBHQ), an Nrf2 agonist, into the Dstr increased the expression of p-Nrf2, HO-1, and GSH-Px, ameliorated ER stress, apoptosis and executive dysfunction caused by METH. Our results indicated that the p-Nrf2/HO-1 pathway was potentially involved in mediating methamphetamine-induced executive dysfunction by inducing endoplasmic reticulum stress and apoptosis in the dorsal striatum.
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This project was supported by the Provincial Natural Science Foundation of Anhui (1908085MH278), Health Research Project of Anhui Province (AHWJ2022a029), Bengbu Medical College's innovative training Program for postgraduate students (Byycx21025, Byycx21037, Byycxz21039, Byycx22086, Byycx22020), Innovative training Program for Chinese College students (202210367035, S202110367098), Anhui Provincial graduate Student Innovation and Entrepreneurship practice Project (2022cxcysj176), and Bengbu Medical College key Laboratory of Addiction Medicine 29-3. All funders didn’t interfere in the study design, collection, analysis, interpretation, or writing of the manuscript.
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The original draft of the work was written by Tao Wei and Jun-Da Li. Dong-Liang Jiao and Xiao-Chu Zhang revised the text critically for essential intellectual content. All authors contributed to the manuscript text, authorized the final version of the manuscript, and participated significantly in its preparation.
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Wei, T., Li, JD., Wang, YJ. et al. p-Nrf2/HO-1 Pathway Involved in Methamphetamine-induced Executive Dysfunction through Endoplasmic Reticulum Stress and Apoptosis in the Dorsal Striatum. Neurotox Res 41, 446–458 (2023). https://doi.org/10.1007/s12640-023-00650-7
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DOI: https://doi.org/10.1007/s12640-023-00650-7