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Neuroreceptor interactions of drugs of abuse to predict human health




Principle investigator: Laura Hondebrink, Ph.D.
Project leader: R.H.S. Westerink, Ph.D. and prof. J. Meulenbelt
Project description:
The aim of this project is to gain insight in the neurophysiological mechanisms underlying the effects of designer drugs during acute, chronic and developmental exposure. Interindividual differences as well as combinations of drugs will also be examined.
Effects on activation/inhibition of postsynaptic neurotransmitter receptors and presynaptic release mechanisms will be investigated. Electrophysiological techniques (voltage clamp, amperometry) will be combined with calcium imaging techniques to determine the mechanisms in which drugs exert their effects.



These techniques will first be applied in in vitro models, and validated using ex vivo brain slices and/or models for neurodevelopment. Interindividual differences in receptor subunit compositions will be examined with a heterologues expression system; Xenopus oocytes. Experiments in a parallel PhD project will be performed in human volunteers; these data will be used to relate mechanistic findings to clinically relevant exposure data.
A large part of the population (~25%) in the Western world has once or more frequently been exposed to cannabis or other drugs of abuse. The use of these drugs of abuse is associated with health problems, addiction and social problems and has major financial consequences for both society and addicted users. Surprisingly, for many designer drugs the working mechanism and the (secondary?) mechanism (s?) causing the adverse health effects are not known. This holds in particular for chronic exposure, developmental exposure and for exposure to mixtures of drugs of abuse (e.g., alcohol and cocaine). Another issue is that many new designer drugs with unknown working mechanism and health effects are put onto the market every year. It should also be noted that some people are more sensitive to these drug effects than other people. It is therefore of importance to study the basis of these inter-individual differences in vulnerability.
Contrasting to these adverse effects, some of these drugs have been ascribed a medicinal and possible neuroprotective effects. Therefore, it has become an urgent matter to advance the understanding of the working mechanisms underlying both the neurotoxic and neuroprotective potential of new and already existing designer drugs.
Recent publications:
- Hondebrink, L., Verboven, A.H., Drega, W.S., Schmeink, S., de Groot, M.W.G.D.M., van Kleef, R.G.D.M., Wijnolts, F.M., de Groot, A., Meulenbelt, J., Westerink, R.H.S. (2016). Neurotoxicity screening of (illicit) drugs using novel methods for analysis of microelectrode array (MEA) recordings. Neurotoxicology 55, 1-9.
- Hondebrink, L., Hermans, E.J., Schmeink, S., van Kleef, R.G.D.M., Meulenbelt, J., Westerink, R.H.S. (2015). Structure-dependent inhibition of the human α1β2γ2 GABAA receptor by piperazine derivatives: a novel mode of action. Neurotoxicology 51, 1-9.
- Hondebrink, L., Tan, S., Hermans, E., van Kleef, R.G.D.M., Meulenbelt, J., Westerink, R.H.S. (2013). Additive inhibition of human α1β2γ2 GABAA receptors by mixtures of commonly used drugs of abuse. Neurotoxicology 35, 23-29.
- Rietjens, S.L., Hondebrink, L., Westerink, R.H.S., Meulenbelt, J. (2012). Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions. Critical Reviews in Toxicology 42, 854-876.
- Hondebrink, L., Meulenbelt, J., Rietjens, S.J., Meijer, M., Westerink, R.H.S. (2012). Methamphetamine, amphetamine, MDMA ('ecstasy'), MDA and mCPP modulate electrical and cholinergic input in PC12 cells. Neurotoxicology 33, 255-260.
- Hondebrink, L., Meulenbelt, J., van Kleef, R.G.D.M., van den Berg, M. and Westerink, R.H.S. (2011) Modulation of human GABAA receptor function: A novel mode of action of drugs of abuse. Neurotoxicology 32, 823-827.
- Hondebrink, L., Meulenbelt, J., Meijer, M., van den Berg, M., Westerink, R.H.S. (2011). High concentrations of MDMA (‘ecstasy’) and its metabolite MDA inhibit calcium influx and depolarization-evoked vesicular dopamine release in PC12 cells. Neuropharmacology 61, 202-208. 
- Westerink, R.H.S., Hondebrink, L. (2010). Are high-throughput measurements of intracellular calcium using plate-readers sufficiently accurate and reliable? Toxicology and Applied Pharmacology 249, 247-248.
- Hondebrink, L., Meulenbelt, J., Timmerman, J.G., van den Berg, M., Westerink, R.H.S. (2009). Amphetamine reduces vesicular dopamine content in PC12 and chromaffin cells only following l-DOPA exposure. Journal of Neurochemistry 111, 624-633.
- National Poison and Information Centre (NVIC), University Medical Center Utrecht (UMCU)