The aim of this project is to gain insight in the neurophysiologic mechanisms 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. Electro-physiological 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. Interindividual differences in receptor subunit compositions will be examined with a heterologues expression system; Xenopus oocytes.

In a later stage, developmental effects will be examined by using embryonic stem cells, which can also reveal possible neuroprotective effects. 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.