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In vitro neurotoxicity of drug of abuse and new psychoactive substances

Principle investigator: Anne Zwartsen, M.Sc 
Project leaders:
Remco Westerink, Ph.D.
Laura Hondebrink, Ph.D.


Project description:
The aim of this project is to extend knowledge about the neurophysiological and neurotoxicological mechanisms and health risks associated with exposure to ‘new psychoactive substances’ (NPS).
In this project, mechanistic in vitro studies will focus on effects of NPS on neuronal activity as well as novel modes of action. Therefore, effects of NPS on electrical activity will be investigated with state of the art multi-electrode array recordings of rat primary cortical neurons as well as human ‘induced pluripotent stem cell’ (hIPSC)-derived neurons. Additionally, effects of NPS on specific modes of action will be assessed, including neurotransmitter transporters as well as clinically relevant neurotransmitter receptors.
Currently, over 400 NPS that may pose a health threat are monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). The use and number of NPS is constantly increasing, and the lifetime prevalence of NPS in young adults increased to nearly 10% in the EU. Similarly, the reported number of intoxications and deaths in Europe related to NPS exposure has increased as well, with NPS accounting for nearly 10% of all drug-related Emergency Department visits in 2014. The negative health effects related to NPS use can be severe, including neurological, psychological and cardiovascular effects. However, the modes of action of most NPS are not well studied. Therefore, it has become an urgent matter to advance the understanding of the mechanisms underlying the neurotoxic potential of NPS.
Within this project, specific expertise on cellular neurophysiological mechanisms and methodologies will therefore be combined with current state of the art (human) in vitro models to identify potential novel modes of action of NPS and to investigate the associated health risks.
Recent publications:
- Zwartsen A, Hondebrink L, de Lange DW, Westerink RHS. Hyperthermia exacerbates the acute effects of psychoactive substances on neuronal activity measured using microelectrode arrays (MEAs) in rat primary cortical cultures in vitro. Toxicol Appl Pharmacol. 397, 115015 (2020).
- Liu F, Westerink RHS. Neurotoxicity of drug of abuse. Neurotoxicology 78, 161-162 (2020).
- Zwartsen A, Olijhoek ME, Westerink RHS, Hondebrink L. Hazard characterization of synthetic cathinones using viability, monoamine reuptake, and neuronal activity assays. Front Neurosci. 14, 9 (2020).
- Zwartsen A, de Korte T, Nacken P, de Lange DW, Westerink RHS, Hondebrink L. (2019) Cardiotoxicity screening of illicit drugs and new psychoactive substances (NPS) in human iPSC-derived cardiomyocytes using microelectrode array (MEA) recordings. Journal of Molecular and Cellular Cardiology 136, 102-112.
- Zwartsen A, Hondebrink L, Westerink RHS (2019). Changes in neuronal activity in rat primary cortical cultures induced by illicit drugs and new psychoactive substances (NPS) following prolonged exposure and washout to mimic human exposure scenarios. Neurotoxicology 74, 28-39.
-Zwartsen A, Litjens CH, Hondebrink L, van den Heuvel JJ, Greupink R, Russel FG, de Lange DW, Legler J, Koenderink JB, Westerink RHS (2019). Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT). Toxicology 422, 69-75.
- Zwartsen A, Hondebrink L, Westerink RHS (2018). Neurotoxicity screening of new psychoactive substances (NPS): Effects on neuronal activity in rat cortical cultures using microelectrode arrays (MEA). NeuroToxicology 66, 87-97.
- Hondebrink L, Zwartsen A, Westerink RHS (2018). Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data. Pharmacology & Therapeutics 182, 193-224.
- Zwartsen A, Verboven AHA, van Kleef RGDM, Wijnolts FMJ, Westerink RHS, Hondebrink L (2017). Measuring inhibition of monoamine reuptake transporters by new psychoactive substances (NPS) in real-time using a high-throughput, fluorescence-based assay. Toxicology In Vitro 45, 60-71.
- Hondebrink L, Kasteel EEJ, Tukker AM, Wijnolts FMJ, Verboven AHA, Westerink RHS (2017). Neuropharmacological characterization of the new psychoactive substance methoxetamine. Neuropharmacology 123, 1-9.