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.
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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
- METH:
-
Methamphetamine
- mTOR:
-
Mammalian target of rapamycin
- MUD:
-
Methamphetamine use disorder
- NP-40:
-
Nonidet P-40
- OAZ1:
-
Ornithine decarboxylase antizyme
- p53:
-
Tumor protein p53
- SA:
-
Self-administration
- SERT:
-
Serotonin transporter
- SS:
-
Shock-sensitive group
- SR:
-
Shock-resistant group
- TH:
-
Tyrosine hydroxylase
- ULK1:
-
Unc51-like autophagy activating kinase 1
- 5-HT:
-
Serotonin
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This research was supported by funds of the Intramural Research Program of the DHHS/NIH/NIDA.
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JLC and SJ conceived the study and designed the methodology. RS performed the RT-PCR and western blot experiments. SJ performed the analyses of the experimental data. JLC and SJ wrote the article with contributions from RS. All authors reviewed the final manuscript.
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Subu, R., Jayanthi, S. & Cadet, J.L. Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum. Arch Toxicol 94, 3515–3526 (2020). https://doi.org/10.1007/s00204-020-02844-w
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DOI: https://doi.org/10.1007/s00204-020-02844-w