Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum
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ORGAN TOXICITY AND MECHANISMS
Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum Rajeev Subu1 · Subramaniam Jayanthi1 · Jean Lud Cadet1 Received: 15 April 2020 / Accepted: 9 July 2020 © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
Abstract Methamphetamine (METH) use disorder (MUD) is often accompanied by psychotic symptoms, cognitive deficits, and pathological changes in the brains of users. Animals that experimenters injected with drugs also show neurodegenerative changes in their brains. Recently, we have been investigating METH-induced molecular and biochemical consequences in animals that had infused themselves with METH using the drug self-administration (SA) paradigm. In that model, footshocks administered contingently help to separate rats that had already escalated their METH intake into resilient-to-drug (shocksensitive, SS) or compulsive (shock-resistant, SR) METH takers. Herein, we used that model to test the idea that compulsive METH takers might show evidence of drug-induced autophagic changes in their brains. There were significant increases in mRNA levels of autophagy-related genes including Atg2a, Atg5, Atg14, and Atg16L1 in the rat dorsal striatum. Levels of two autophagy biomarkers, autophagy activating kinase (ULK1) and phospho-Beclin1, were also increased. In addition, we found increased p53 but decreased Bcl-2 protein levels. Moreover, the expression of cleaved initiator caspase-9 and effector caspase-6 was higher in compulsive METH takers in comparison to shock-sensitive rats. When taken together, these results suggest that the striata of rats that had escalated and continue to take METH compulsively the presence of adverse consequences exhibit some pathological changes similar to those reported in post-mortem human striatal tissues. These results provide supporting evidence that compulsive METH taking is neurotoxic. Our observations also support the notion of developing neuro-regenerative agents to add to the therapeutic armamentarium against METH addiction. Keywords Substance use disorder · Punishment · Self-administration · Addiction · Transcription factors Abbreviations Atg Autophagy-related gene B2M Beta-2 microglobulin BCL-2 B-cell lymphoma 2 BECN1 Beclin-1 CT Control group DA Dopamine DAT Dopamine transporter DSM-V Diagnostic and Statistical Manual of Mental Disorders V LC3-II Microtubule-associated light chain 3 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02844-w) contains supplementary material, which is available to authorized users. * Jean Lud Cadet [email protected] 1
Molecular Neuropsychiatry Research Branch, DHHS/ NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA
METH Methamphetamine mTOR Mammalian target of rapamycin MUD Methamphetamine use disorder NP-40 Nonidet P-40 OAZ1 Ornithine decarboxylase antizyme p53 Tumor protein
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