Anne Zwartsen, Utrecht University
Conference: International Neurotoxicology Association 17 Meeting, Duesseldorf, Germany
Abstract Title: Is the decrease in in vitro neuronal activity reversible following acute and prolonged exposure to new psychoactive substances (NPS)?
Abstract: The use of new psychoactive substances (NPS) is increasing despite associated health risks and limited pharmacological and toxicological knowledge. Many NPS inhibit and modulate specific targets like monoamine reuptake transporters and receptors following acute exposure, resulting in their adverse and desired effects. In previous research we showed that NPS can also affect 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 (mwMEA). To investigate the reversibility of effects, neuronal activity was also measured after a washout period of 19 h, i.e. 24 h after the start of exposure. During acute exposure, all drugs concentration-dependently decreased neuronal activity. Compared to acute exposure, prolonged exposure did not further exacerbate neurotoxicity. Following washout, effects of 4 out of 11 drugs (methamphetamine, cocaine, methylone and benzylpiperazine) were fully reversible, whereas for all other drugs (partial) recovery was seen. Remarkably, neuronal activity in networks exposed to TFMPP and MDMA did not fully recovery at brain concentrations during recreational drug use. Moreover, after the washout of methylone at relevant human concentrations, neuronal activity even increased. The ability of a neuronal network to regain activity or become overactive after exposure appears independent of drug class, chemical structure, and of IC50 values for acute and prolonged exposure. As such, supplementing the (acute and prolonged) exposure scenario with a washout period allows investigation of the reversibility of effects, in combination with hazard characterization. Even though neuronal activity (partly) recovers after washout following exposure to most drugs, it is disturbing that complete recovery of neuronal activity is observed only for a minority of the tested drugs.