Neurotoxicity screening of (illicit) drugs using novel methods for analysis of microelectrode array (MEA) recordings

Autor: Hondebrink, L, Verboven, A.H.A., Drega, W S, Schmeink, S, de Groot, Martje, van Kleef, R G D M, Wijnolts, F M J, de Groot, Aart, Meulenbelt, J, Westerink, R H S, Pharmacology, Dep IRAS, Sub BasicPharmacology&Psychopharmacology, Sub IRAS Tox CMT/NTX, LS IRAS Tox KTX (Klinische toxicologie)
Přispěvatelé: Pharmacology, Dep IRAS, Sub BasicPharmacology&Psychopharmacology, Sub IRAS Tox CMT/NTX, LS IRAS Tox KTX (Klinische toxicologie)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
GABA Plasma Membrane Transport Proteins
Time Factors
Tyrosine 3-Monooxygenase
Neurotoxicity screening
GABA Agents
Illicit drugs
Drug Evaluation
Preclinical
Action Potentials
Pharmacology
Toxicology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Neuromodulation
Glial Fibrillary Acidic Protein
Journal Article
medicine
Animals
Premovement neuronal activity
Rats
Wistar
Amphetamine
6-Cyano-7-nitroquinoxaline-2
3-dione
Cerebral Cortex
Neurons
Characterisation
General Neuroscience
Glutamate receptor
Neurotoxicity
MDMA
Bicuculline
medicine.disease
Rats
030104 developmental biology
medicine.anatomical_structure
Animals
Newborn
chemistry
Astrocytes
Integrated testing strategy
Vesicular Glutamate Transport Protein 1
CNQX
Analysis strategy
Dizocilpine Maleate
Excitatory Amino Acid Antagonists
Microelectrodes
Neuroscience
030217 neurology & neurosurgery
medicine.drug
Zdroj: NeuroToxicology, 55, 1. Elsevier bedrijfsinformatie b.v.
Neurotoxicology, 55, 1. Elsevier
ISSN: 0161-813X
Popis: Annual prevalence of the use of common illicit drugs and new psychoactive substances (NPS) is high, despite the often limited knowledge on the health risks of these substances. Recently, cortical cultures grown on multi-well microelectrode arrays (mwMEAs) have been used for neurotoxicity screening of chemicals, pharmaceuticals, and toxins with a high sensitivity and specificity. However, the use of mwMEAs to investigate the effects of illicit drugs on neuronal activity is largely unexplored. We therefore first characterised the cortical cultures using immunocytochemistry and show the presence of astrocytes, glutamatergic and GABAergic neurons. Neuronal activity is concentration-dependently affected following exposure to six neurotransmitters (glutamate, GABA, serotonin, dopamine, acetylcholine and nicotine). Most neurotransmitters inhibit neuronal activity, although glutamate and acetylcholine transiently increase activity at specific concentrations. These transient effects are not detected when activity is determined during the entire 30min exposure window, potentially resulting in false-negative results. As expected, exposure to the GABAA-receptor antagonist bicuculline increases neuronal activity. Exposure to a positive allosteric modulator of the GABAA-receptor (diazepam) or to glutamate receptor antagonists (CNQX and MK-801) reduces neuronal activity. Further, we demonstrate that exposure to common drugs (3,4-methylenedioxymethamphetamine (MDMA) and amphetamine) and NPS (1-(3-chlorophenyl)piperazine (mCPP), 4-fluoroamphetamine (4-FA) and methoxetamine (MXE)) decreases neuronal activity. MXE most potently inhibits neuronal activity with an IC50 of 0.5μM, whereas 4-FA is least potent with an IC50 of 113μM. Our data demonstrate the importance of analysing neuronal activity within different time windows during exposure to prevent false-negative results. We also show that cortical cultures grown on mwMEAs can successfully be applied to investigate the effects of different (illicit) drugs on neuronal activity. Compared to investigating multiple single endpoints for neurotoxicity or neuromodulation, such as receptor activation or calcium channel function, mwMEAs can provide information on integrated aspects of drug-induced neurotoxicity more rapidly. Therefore, this approach could contribute to a faster insight in possible health risks and shorten the regulation process.
Databáze: OpenAIRE
Externí odkaz: