Keynote Lecture Mechanisms of Cannabin Action on the Brain

Earlier results from our laboratory demonstrated that the mechanism by which both endoand exogenous cannabinoids interfer with network oscillations and associated cognitive functions is through the reduction of basket cell-mediated GABAergic inhibition and glutamatergic excitation in the cerebral cortex via presynaptic CB1 cannabinoid receptors. Combined molecular anatomy and electrophysiology revealed that the endocannabinoid involved in the physiological control of synaptic transmission is 2-arachidonoyl glycerol (2-AG). The synthesising enzyme of 2-AG (diacyl glycerol lipase, DGL) is located postsynaptically, whereas its site of action (the CB1cannabinoid receptor), as well as its metabolizing enzyme (monacyl glycerol lipase, MGL), are located presynaptically. This arrangement provides further evidence for the retrograde nature of endocannabinoid actions in the shortterm regulation of synaptic efficacy, a phenomenon termed depolarization-induced suppression of inhibition (DSI) or excitation (DSE). This type of signaling allows neurons to regulate their own inputs in an activity-dependent manner. The efficient endocannabinoid-mediated control of the two major antagonistic transmitter systems (GABA and glutamate) in the cortex raised the possibility of a crucial involvement of this signaling mechanism in the patho-mechanism of various disorders of the central nervous system. Several lines of evidence will be reviewed in the lecture to support this hypothesis in the relation to epilepsy, anxiety and drug addiction.