Within neurons of the central nervous system, initiation of eCB signaling results in retrograde inhibition of afferent neurotransmission. Specifically, post-synaptic eCB synthesis, initiated via voltage-dependent calcium channel activation or G-protein coupled receptor (GPCR)-dependent mechanisms, results in release and diffusion of eCBs into the synaptic cleft (Kano et al., 2009). Thereafter, eCBs bind to the CB1 receptor localized to axon terminals of glutamatergic and GABAergic neurons, thus activating intracellular signaling downstream of Gi/o proteins and causing either short-term or long-term suppression of vesicular neurotransmitter release (Chevaleyre et al., 2006). This signaling motif has been described in numerous brain regions including the brainstem, midbrain, cerebellum, hippocampus, striatum, and neocortex. The widespread distribution of eCB-mediated synaptic signaling underscores the pleiotropic functions of eCBs in the regulation of motor control, learning and memory, pain, motivation, metabolic integration, and affect regulation (see (Kano et al., 2009)).
