Abstract
An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of “homemade” methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the ‘homemade’ drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the ‘homemade’ mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the ‘homemade’ mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.
Highlights
Abuse of a ‘homemade’ version of the psychostimulant drug methcathinone (Mcat) causes a persistent and disabling extrapyramidal syndrome (Sikk et al 2011, 2013; Stepens et al 2014).This shares some common features with Parkinson’s disease, but has distinct symptoms including early falls, dystonia, severe dysarthria, and a poor response to l-DOPA treatment (Sikk et al 2011)
We have shown that the counting of dopaminergic neurons at the third cranial nerve provide a reliable anatomical landmark that reflects the extent of cell loss through the entire substantia nigra pars compacta (SNpc) (Iravani et al 2002; Bukhatwa et al 2009), suggesting that the cell counting at the level of third cranial nerve is an alternative method of determining cell loss in comparison with stereological counting
SPECT imaging demonstrated a significant decrease in specific to nonspecific epidepride binding ratio in Mcat (1.85; 95% CI 0.9–2.7), Mn (1.61; 95% CI 0.7–2.5) and Mcat/Mn (2.06; 95% CI 1.5–2.7) groups compared to the controls
Summary
Abuse of a ‘homemade’ version of the psychostimulant drug methcathinone (Mcat) causes a persistent and disabling extrapyramidal syndrome (Sikk et al 2011, 2013; Stepens et al 2014).This shares some common features with Parkinson’s disease, but has distinct symptoms including early falls, dystonia, severe dysarthria, and a poor response to l-DOPA treatment (Sikk et al 2011). Mn impairs the release of dopamine without causing a significant loss of nigro-striatal dopaminergic neurons (Guilarte 2013) This would fit with the fact that ‘homemade’ Mcat produced using sodium dichromate as the oxidizing agent, does not appear to have the same toxic effects. Mcat itself causes striatal dopamine release and inhibits its reuptake after both acute and chronic administration (Cozzi et al 2013) and its potential toxicity on longer term administration is unclear. This raises the possibility that effects of ‘homemade’ Mcat seen in man are either due to Mn toxicity or to the actions of Mcat or to a synergistic interaction.
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