Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity.

Milo Grotell,Markus M Forsberg,Elena De Miguel,Esko Kankuri,Mateusz Dudek,Aaro Jalkanen,Mikko I Kettunen,Esa R Korpi,Essi Törrönen,Petri Hyytiä,Bjørnar Den Hollander,Jouni Ihalainen

doi:10.3389/fphar.2021.679759

Milo Grotell, Markus M Forsberg + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2021.679759

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Abstract

Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.

Highlights

During the last couple of decades, there has been an increasing supply of substituted cathinones in the illegal drug market (Vardakou et al, 2011; Deluca et al, 2012; EMCDDA, 2018)
Post-hoc testing revealed a significant decrease in body temperature vs. vehicle only in the group treated with EtOH, whereas a significant increase in body temperature was observed in all other groups that received METH or 4-MMC (Figure 2)
We show that co-administration of EtOH with 4-MMC in a binge-abuse model produces a widespread pattern of neuronal deactivation in monoamine-rich brain areas when assessed with manganese-enhanced magnetic resonance imaging (MEMRI) two weeks after the last drug administration

Summary

Introduction

During the last couple of decades, there has been an increasing supply of substituted cathinones in the illegal drug market (Vardakou et al, 2011; Deluca et al, 2012; EMCDDA, 2018) These substances initially gain popularity as legal alternatives to existing amphetamine-type stimulants. 4-MMC shows many pharmacological similarities with methamphetamine (METH), with both substances producing rapid and substantial increases in accumbal extracellular dopamine (DA) and serotonin levels in vivo (Kehr et al, 2011). The effects of both METH and 4-MMC are mainly mediated via increased release and blockade of reuptake of DA (Cho and Melega, 2002; Winstock et al, 2011b; Hadlock et al, 2011; Lopez-Arnau et al, 2012; MartinezClemente et al, 2012; Korpi et al, 2015). 4-MMC neurotoxicity can be precipitated when the drug is administered under circumstances known to exacerbate stimulant neurotoxicity, such as high ambient temperatures (Hadlock et al, 2011; Lopez-Arnau et al, 2015; Pantano et al, 2017)

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