Cannabinoid CB1 receptor signaling in the brain: the where matters
Giovanni Marsicano, DVM, PhD
Endocannabinoid and Neuroadaptation Group,
U1215 Inserm & Université de Bordeaux
Cannabinoid drugs (e.g. the active principle of the plant cannabis, 9-tetrahydrocannabinol, THC) exert several effects on the brain via the activation of the G protein-coupled type-1 cannabinoid receptors (CB1). On the other hand, CB1 receptors are part of a physiological system (the endocannabinoid system, or ECS), through which the particular endogenous signaling molecules (the endocannabinoids) control a plethora of brain functions. The effects of exogenous cannabinoids and the physiological roles of the ECS are only partially overlapping. This is likely due to the fact that the ECS has patterns of activation that are extremely regulated in time and space, features that are obviously overcome by massive stimulation of CB1 receptors by exogenous drugs. During the last years, my laboratory contributed to the understanding of the mechanisms underlying both pharmacological effects of cannabinoids and the physiological functions of the ECS. In particular, we dissected the impact of CB1 receptors expressed in different brain cell types and regions in these effects and functions. More recently, we identified a novel mode of action of CB1 receptors, namely the control of mitochondrial bioenergetic activity as a mean to regulate brain cellular and cognitive processes. In this lecture, I will present an excursus of our studies on the mechanisms of action of CB1 receptors in the brain, both from the pharmacological and physiological points of view. Special attention will be dedicated to the new results revealing the CB1-dependent control of mitochondrial activity as a novel paradigm of G protein-coupled receptor control of brain functions.