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

Anne Zwartsen,Laura Hondebrink,Remco Hs Westerink

doi:10.1016/j.neuro.2019.05.004

Anne Zwartsen, Laura Hondebrink + Show 1 more

Open Access

https://doi.org/10.1016/j.neuro.2019.05.004

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Abstract

The use of new psychoactive substances (NPS) is increasing despite associated health risks and limited pharmacological and toxicological knowledge. Information is available mainly for acute effects on specific targets like monoamine transporters and receptors. Recently, we have shown the ability of several NPS and illicit drugs to modulate neuronal activity during acute exposure. While these acute measurements provide valuable information regarding the potency and possible structure-activity relationships, an exposure scenario more representative of human exposure would increase insight and aid translation to the human situation.Therefore, we investigated the effects on neuronal activity after acute (30 min) and prolonged (5 h) exposure to amphetamine-type stimulants, cathinones, hallucinogens, piperazines and cocaine using rat primary cortical cultures grown on multi-well microelectrode arrays. To investigate the reversibility of effects, activity was also measured after a washout period of 19 h.During acute exposure, all compounds concentration-dependently decreased neuronal activity. Compared to acute exposure, prolonged exposure did not further decrease neuronal activity. Following washout, effects of 3 out of 11 drugs (methamphetamine, cocaine, and benzylpiperazine) were fully reversible, whereas effects induced by MDMA, PMMA and α-PVP were partially reversible. Neuronal activity did not recover after 19 h washout following exposure to the highest concentration of MDPV, 2C-B, 25B-NBOMe, and TFMPP. On the contrary, exposure to low concentrations of methylone, and to some extent of 2C-B, increased neuronal activity after the washout period.Hazard characterization of emerging NPS should include at least an acute exposure to determine a potency rank order. Supplementing the (acute and prolonged) exposure scenario with a washout period allows investigation of the reversibility of effects. The possibility of a neuronal network to regain activity after drug exposure appears independent of drug class or IC50 values for acute and prolonged exposure. Even though neuronal activity (partly) recovers after washout following exposure to most drugs, it is perturbing that complete recovery of neuronal activity is observed only for a minority of the tested drugs.

Highlights

Despite the associated health and addiction risks, the recreational use of illicit drugs remains popular
The presence of monoaminergic receptors, transporters and synthesis pathways is not as pronounced in cortical cultures compared to for instance dopaminergic regions (Osredkar and Krzan, 2009), we have previously shown that these cultures are responsive to dopamine and serotonin (Hondebrink et al, 2016) and can be used to investigate the acute neurotoxicity and potency of a range of illicit drugs and new psychoactive substances (NPS) (Zwartsen et al, 2018; Hondebrink et al, 2016)
We have previously shown that several illicit drugs and NPS concentration-dependently decrease neuronal activity after acute (30 min) exposure and that their potency to inhibit neuronal activity could be related to chemical classes or structures (Zwartsen et al, 2018)

Summary

Introduction

Despite the associated health and addiction risks, the recreational use of illicit drugs remains popular. Of the adults (15–64 years) in the European Union, > 25% are estimated to have used illicit drugs at least once (EMCDDA, 2018). In recent years, emerging new psychoactive substances (NPS) gained popularity as a drug of choice as alternatives for illicit drugs. Since 2009, over 800 different NPS have been reported (UNODC, 2018), which can be divided into cathinones, phenethylamines, arylcyclohexylamines, benzodiazepines, opioids, and synthetic cannabinoids. Almost 70% of these compounds were detected in the last five years and around 400 of these compounds are reported on a yearly basis (EMCDDA, 2018). The number of NPS is still increasing with around one novel NPS reported to the European monitoring center every week (EMCDDA, 2018)

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