Abstract
Synthetic cathinones are the second largest class of new psychoactive substances (NPS) on the drug market. Despite the large number of different cathinones and their abundant use, hazard characterization is mainly limited to their potential to inhibit monoamine transporters. To expand the current hazard characterization, we first investigated the acute effects of several synthetic cathinones [4-methylethcathinone (4-MEC), 3-methylmethcathinone (3-MMC), 4-MMC, methylone, pentedrone, α-pyrrolidinovalerophenone (α-PVP), and 3,4-methylenedioxypyrovalerone (MDPV)] on human dopamine, norepinephrine, and serotonin reuptake transporters (hDAT, hNET, and hSERT), which were stably transfected in human embryonic kidney (HEK) 293 cells. Next, we examined effects on spontaneous neuronal activity in rat primary cortical cultures grown on microelectrode arrays (MEAs) as an integrated endpoint for neurotoxicity. Changes in neuronal activity were assessed after acute (30 min) and prolonged (4.5 h) exposure. Moreover, we investigated whether neuronal activity recovered after washout of the exposure (24 h after the start of the 5 h exposure). Low micromolar concentrations of synthetic cathinones inhibited monoamine uptake via hDAT and hNET, while higher cathinone concentrations were needed to inhibit uptake via hSERT. Comparable high concentrations were needed to inhibit spontaneous neuronal activity during acute (30 min) and prolonged (4.5 h) exposure. Notably, while the inhibition of neuronal activity was reversible at low concentrations, only partial recovery was seen following high, but non-cytotoxic, concentrations of synthetic cathinones. Synthetic cathinones with either a pyrrolidine moiety or long alkyl-tail carbon chain more potently inhibit monoamine uptake via hDAT and neuronal activity. Monoamine uptake via hNET was most potently inhibited by synthetic cathinones with a pyrrolidine moiety. The combination of integrated measurements (MEA recordings of neuronal activity) with single target assays (monoamine reuptake transporter inhibition) indicates inhibition of hDAT and hNET as the primary mode of action of these synthetic cathinones. Changes in neuronal activity, indicative for additional mechanisms, were observed at higher concentrations.
Highlights
IntroductionNew psychoactive substances (NPS) have acquired a steady interest and place on the drug market
Over the last decade, new psychoactive substances (NPS) have acquired a steady interest and place on the drug market
All cathinones inhibited monoamine uptake via hDAT, hNET, and hSERT (Figure 2; data for α-PVP re-analyzed from Zwartsen et al, 2017)
Summary
New psychoactive substances (NPS) have acquired a steady interest and place on the drug market. Synthetic cathinones are the most popular and abundant class of NPS on the drug market (United Nations Office on Drugs and Crime [UNODC], 2017). At the end of 2017, 148 synthetic cathinones were monitored by the United Nations Office on Drugs and Crime (United Nations Office on Drugs and Crime [UNODC], 2018). Novel synthetic cathinones were introduced, starting with mephedrone (4-MMC) in 2006. In the following year, when mephedrone popularity peaked, novel cathinones methylone, 3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinovalerophenone (α-PVP), pentedrone, 3-methylmethcathinone (3-MMC), and 4-methylethcathinone (4-MEC) were introduced to the drug market (Hondebrink et al, 2018; Majchrzak et al, 2018). The cathinone market peaked in 2014 when 30 novel synthetic cathinones were notified to the EU Early Warning System (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2018)
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