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Increased striatal VMAT2 binding in mice after chronic administration of methcathinone and manganese
Andres Asser1, Sulev Kõks2, Anniina Snellman3
1Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia.
Abstract:
Intravenous use of a psychostimulant drug containing methcathinone (ephedrone) and manganese causes an irreversible extrapyramidal syndrome in drug abusers. We aimed to reproduce the syndrome in mice to evaluate dopaminergic damage. C57/B6 mice were intraperitoneally injected once a day with the study drug or saline for a period of 27 weeks. Motor activity was recorded in an automated motility-box. After 13 and 27 weeks of treatment, ex vivo digital autoradiography was performed using [11C]dihydrotetrabenazine ([11C]DTBZ). After 27 weeks of treatment [11C]DTBZ autoradiography demonstrated a significant increase in the striatum-to-cerebellum binding ratio compared with saline treated controls. At the same time point, there was no evident change in motor activity. Increased [11C]DTBZ binding may indicate vesicular monoamine transporter type 2 (VMAT2) function is altered. The lack of extrapyramidal symptoms in animals could be attributed to low dosing regimen or high metabolic rate.
Insights
Intravenous drug abuse of methcathinone and manganese may alter brain function, specifically vesicular monoamine transporter type 2 (VMAT2). This study explored potential dopaminergic damage in mice, revealing altered VMAT2 function without observable motor deficits.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Intravenous administration of psychostimulant drugs containing methcathinone (ephedrone) and manganese is linked to irreversible extrapyramidal syndrome in humans.
- Dopaminergic system damage is a suspected mechanism underlying this neurotoxic effect.
Purpose of the Study:
- To establish a mouse model for investigating the neurotoxic effects of methcathinone and manganese.
- To evaluate the impact of chronic drug administration on dopaminergic pathways and motor function.
Main Methods:
- C57/B6 mice received daily intraperitoneal injections of the study drug or saline for 27 weeks.
- Motor activity was assessed using an automated motility-box.
- Ex vivo digital autoradiography with [¹¹C]dihydrotetrabenazine ([¹¹C]DTBZ) was performed at 13 and 27 weeks.
Main Results:
- After 27 weeks, [¹¹C]DTBZ autoradiography showed a significant increase in the striatum-to-cerebellum binding ratio in treated mice compared to controls.
- No significant changes in motor activity were observed at the 27-week time point.
- The increased [¹¹C]DTBZ binding suggests altered function of the vesicular monoamine transporter type 2 (VMAT2).
Conclusions:
- Chronic administration of methcathinone and manganese in mice alters VMAT2 binding in the striatum.
- The absence of overt extrapyramidal symptoms in the animal model may be due to the specific dosing regimen or the animals' metabolic rate.
- This model provides a basis for further research into the neurotoxic mechanisms of combined drug exposure.
