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Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum

A figure from this study.Featured Paper of the Month – January 2021

The use of  methamphetamine (METH) is very prevalent throughout the world. METH can cause anxiety, psychosis, seizures, and death. Previous research in the Cadet Lab has shown that METH can cause neurodegeneration when the drug is injected by investigators.  It was therefore important to find out if there is degeneration in the brains of rats that learn to give themselves METH by a behavioral technique called self-administration (SA).  In that model, rats are trained to self-administer METH and then get footshocks as punishment to see if they will stop or continue to take the drug. In general, 40% of rats will continue to take METH compulsively even in the presence of the shocks. We found that animals that continue to take METH have changes in the brain expression of some genes, namely Atg5, Atg14, and Atg16L1, that are related to a process called autophagy. Abnormalities in autophagy have been reported in some neurological diseases. The brains of the compulsive METH takers also show increases in the levels of some proteins involved in regulating autophagy. Moreover, these compulsive METH takers showed increased expression of proteins involved in causing cell death but decreased in a protein called Bcl-2 that protects against cell death.  These results tell us that compulsive METH taking can result in pathological changes similar to what is reported when investigators give the drug to rats. These observations also tell us that we need to develop treatments that can help the brains of users who take too much METH.

Publication Information

Subu, Rajeev; Jayanthi, Subramaniam; Cadet, Jean Lud

Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum Journal Article

In: Archives of Toxicology, vol. 94, no. 10, pp. 3515–3526, 2020, ISBN: 1432-0738.

Abstract | Links

@article{Subu:2020aa,
title = {Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum},
author = {Rajeev Subu and Subramaniam Jayanthi and Jean Lud Cadet},
url = {https://pubmed.ncbi.nlm.nih.gov/32676729/},
doi = {10.1007/s00204-020-02844-w},
isbn = {1432-0738},
year = {2020},
date = {2020-01-01},
journal = {Archives of Toxicology},
volume = {94},
number = {10},
pages = {3515--3526},
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 (shock-sensitive, 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 = {},
pubstate = {published},
tppubtype = {article}
}

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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 (shock-sensitive, 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.

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  • https://pubmed.ncbi.nlm.nih.gov/32676729/
  • doi:10.1007/s00204-020-02844-w

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