Cannabinoids:  What in vitro studies have not told us.   Dr. Gernot Riedel (University of Aberdeen, Aberdeen, UK.) Dr. Robert E Hampson (Wake Forest University School of Medicine, Dept. Physiology & Pharmacology, Winston-Salem, USA.)

Recently, the Food and Drug Agency (FDA) qualified a novel cannabinoid receptor antagonist from Sanofi-Aventis as approvable in the treatment of obesity and addiction and this has brought research into endocannabinoid function back into centre stage. Recent advances in understanding the function of the endocannabinoid system in the brain, however, mainly arose from studies using in vitro, ex vivo, and cell based assays.  These, however, often fail to be confirmed by in vivo investigations.  For example:     1) In vitro slice work has now firmly established that cannabinoids contribute to depolarisation-induced suppression of inhibition (DSI) in the hippocampus.  However, recordings from freely moving animals show that induction protocol for DSI are non-physiological and the phenomenon may not exist in a living animal, with the corollary that endocannabinoids may not contribute to this mechanism.     2) Cell-based assays show that very low doses of cannabis (or synthetic agonists of cannabinoid receptors) are neurotoxic, while higher doses are neuroprotective.  At the same time, low doses have little or no effect on memory formation although this would be expected given that hippocampal cells are highly vulnerable to this treatment.  By contrast, high doses of cannabinoids that should protect neurons, in fact lead to memory impairment.     These two examples highlight the need for a wider and more detailed analysis into the function of the endocannabinoid system using systemic approaches.  Towards this end, we have selected four important areas of research from which a major contribution toward a richer understanding of cannabinoid function and potential treatments can be expected.  These areas include cognition, physiology of cell ensembles, neuro-imaging and addiction.  At the same time, these areas cannot be simply substituted by in vitro models.  Liana Fattore: Endocannabinoids and addiction: a chance for some treat Andrew Horti: Imaging of the brain cannabinoid system. Robert E. Hampson: Role of brain cannabinoids in shaping ensemble responses to behavioural conditions. Gernot Riedel: Endocannabinoid function in cognition.