Abstract
While the prevalence and the use of new psychoactive substances (NPS) is steadily increasing, data on pharmacological, toxicological and clinical effects is limited. Considering the large number of NPS available, there is a clear need for efficient in vitro screening techniques that capture multiple mechanisms of action. Neuronal cultures grown on multi-well microelectrode arrays (mwMEAs) have previously proven suitable for neurotoxicity screening of chemicals, pharmaceuticals and (illicit) drugs. We therefore used rat primary cortical cultures grown on mwMEA plates to investigate the effects of eight NPS (PMMA, α-PVP, methylone, MDPV, 2C-B, 25B-NBOMe, BZP and TFMPP) and two ‘classic’ illicit drugs (cocaine, methamphetamine) on spontaneous neuronal activity.All tested drugs rapidly and concentration-dependently decreased the weighted mean firing rate (wMFR) and the weighted mean burst rate (wMBR) during a 30 min acute exposure. Of the ‘classic’ drugs, cocaine most potently inhibited the wMFR (IC50 9.8 μM), whereas methamphetamine and the structurally-related NPS PMMA were much less potent (IC50 100 μM and IC50 112 μM, respectively). Of the cathinones, MDPV and α-PVP showed comparable IC50 values (29 μM and 21 μM, respectively), although methylone was 10-fold less potent (IC50 235 μM). Comparable 10-fold differences in potency were also observed between the hallucinogenic phenethylamines 2C-B (IC50 27 μM) and 25B-NBOMe (IC50 2.4 μM), and between the piperazine derivatives BZP (IC50 161 μM) and TFMPP (IC50 19 μM). All drugs also inhibited the wMBR and concentration-response curves for wMBR and wMFR were comparable.For most drugs, IC50 values are close to the estimated human brain concentrations following recreational doses of these drugs, highlighting the importance of this efficient in vitro screening approach for classification and prioritization of emerging NPS. Moreover, the wide range of IC50 values observed for these and previously tested drugs of abuse, both within and between different classes of NPS, indicates that additional investigation of structure-activity relationships could aid future risk assessment of emerging NPS.
Highlights
Over the past 5 years, the proportion of the general population (15–64 years) that used a drug at least once has been stable at approximately 5% (UNODC, 2017)
As the prevalence and use of new psychoactive substances (NPS) is continuously increasing, we investigated the acute effects of 10 NPS and’ classic’ illicit drugs on spontaneous neuronal activity at human relevant concentrations
Active wells were exposed for 30 min to different concentrations of cocaine, methamphetamine, PMMA, methylone, MDPV, a-PVP, 2C-B, 25B-NBOMe, BZP
Summary
Over the past 5 years, the proportion of the general population (15–64 years) that used a drug at least once has been stable at approximately 5% (UNODC, 2017). The second most used class of drugs are the amphetamines and their use, methamphetamine, has been increasing in some European countries (UNODC, 2017). A. Zwartsen et al / NeuroToxicology 66 (2018) 87–97 proportion of the market, NPS encompass a group of over 700 different substances. Zwartsen et al / NeuroToxicology 66 (2018) 87–97 proportion of the market, NPS encompass a group of over 700 different substances These potentially harmful drugs are manufactured to have intended effects comparable to those of illegal drugs like amphetamine, lysergic acid diethylamide (LSD), ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Some of the NPS that stayed on the market, like alpha-pyrrolidinovalerophenone (a-PVP), benzylpiperazine (BZP), 3,4-methylenedioxypyrovalerone (MDPV), mephedrone, methylone and PMMA, have been classified as illegal drugs by authorities in several countries including the UK, Canada, Australia and many European countries (UNODC, 2017)
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