As part of a project financed by Top Institute Pharma (TIP) we are studying the role of endocannabinoids
(eCB) in signalling processes in the prefrontal cortex (PFC). Seven Dutch research groups participate in this
project to address the role of the brain eCB system in the regulation of mesocorticolimbic neurotransmission
and the therapeutic opportunities of cannabinoid ligands. To that end, multiple modalities will be used to
study a specific set of brain functions implicated in psychopathological syndromes with high medical need.
In this respect, behavioural models matched between humans and animals, together with dissecting in-vitro
approaches, will allow for a high degree of cross-translation and rapid exchange of new findings between
the seven research groups involved and will bundle the expertise available at all levels of integration
on this specific topic in The Netherlands.
Understanding the CB system in, behavioural, electrophysiological and neurochemical terms in animals and humans will result in the validation of CB related targets (and resultant assays) for the treatment of addictive behaviours (smoking and alcoholism), impulse control and cognitive disorders. Functional MRI, measurement of blood eCB levels, coupled to psychological questionnaires and tasks in humans will be used to evaluate the role of the eCB system in these disorders. Taken together, this strategy is expected to increase the drug-ability of the CB system by providing an empirical basis for new and promising applications of CB ligands.
Electrical activity recorded from PFC neurons.
Panel on the left shows three biocytin filled layer 5 neurons from which recordings were made.
Right panels: spiking activity recorded under current clamp conditions (top);
synaptic currents recorded under voltage clamp conditions (bottom)
With electrophysiological and imaging methods in our lab the role of eCB-mediated modulation
of neurotransmission will be addressed in two PhD projects. The first one will also apply
microdialysis and glutamate sensor methods (collaboration with RUG) and the second one is concentrated
around the behavioural paradigms developed at UMC/VUMC.
The modulatory actions of eCB’s and CB1 ligands at the cellular level will be investigated in several
subregions of the PFC thought be involved in drug abuse.
The priority of subregions to investigate will be based on the information available at the behavioral
level, in particularly in relation to the possibilities for eCB modulation. We will also explore the
modulatory role of the CB1 receptor on the dopamine and glutamatergic response in relation to several
forms of plasticity: learning and memory, adaptation and plasticity, in close relation with the
behavioural experiments at UMC/VUMC. The in vitro approach will provide the opportunity to investigate
basic mechanisms involved in the interactions and modulations of the CB/eCB system, with a much better
pharmacological access and the possibility to optimally employ the sensing capacities developed in the
Groningen project (RUG).
At this point in time (September 2007) the first project has started and the preliminary experiments
regarding eCB signalling have been performed. With whole-cell recording methods PFC neuron activity
can be measured (see figure) and we are investigating how eCBs can affect PFC excitability.
Taco Werkman, PhD
Center for Neuroscience, Swammerdam Institute for Life Sciences
University of Amsterdam
Science Park 904
1098 XH Amsterdam
The Netherlands
Phone: +31-20-5257632
Fax: +31-20-5257709
e-mail
This page was last updated on 14 march 2010