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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum
Rajeev Subu1, Subramaniam Jayanthi1, Jean Lud Cadet2
1Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
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.
Insights
Compulsive methamphetamine (METH) use in rats shows increased autophagy and cell death markers in the brain, suggesting neurotoxicity. These findings support developing neuro-regenerative treatments for METH addiction.
Area of Science:
- Neuroscience
- Molecular Biology
- Addiction Research
Background:
- Methamphetamine (METH) use disorder is linked to psychosis, cognitive deficits, and brain pathology.
- Previous research indicates neurodegenerative changes in animal models following drug administration.
- The self-administration (SA) paradigm with contingent footshocks differentiates METH intake into resilient (SS) and compulsive (SR) patterns.
Purpose of the Study:
- To investigate if compulsive METH takers exhibit drug-induced autophagic changes in the brain.
- To explore molecular and biochemical consequences of METH self-administration in distinct rat phenotypes.
Main Methods:
- Utilized the METH self-administration (SA) paradigm with contingent footshocks to categorize rats into shock-sensitive (SS) and shock-resistant (SR) groups.
- Analyzed mRNA levels of autophagy-related genes (Atg2a, Atg5, Atg14, Atg16L1) in the rat dorsal striatum.
- Measured protein levels of autophagy biomarkers (ULK1, phospho-Beclin1), apoptosis markers (p53, Bcl-2), and caspases (caspase-9, caspase-6).
Main Results:
- Significant increases in mRNA levels of autophagy-related genes (Atg2a, Atg5, Atg14, Atg16L1) were observed in the dorsal striatum of compulsive METH takers.
- Elevated levels of autophagy biomarkers (ULK1, phospho-Beclin1) and increased p53 with decreased Bcl-2 protein were found.
- Higher expression of cleaved initiator caspase-9 and effector caspase-6 indicated increased apoptosis in compulsive METH takers compared to resilient rats.
Conclusions:
- Compulsive METH use in rats is associated with pathological autophagic and apoptotic changes in the striatum, mirroring findings in human post-mortem tissues.
- These results provide evidence that compulsive METH taking is neurotoxic.
- The study supports the development of neuro-regenerative agents as a therapeutic strategy for METH addiction.
