The mode of action of the eCBs on their receptors (Figure 1) reveals that eCBs synthesized in postsynaptic neurons act pre-synaptically at CB1Rs in a retrograde mode [46]. There are data showing that eCBs can also activate localized CB1Rs post-synaptically [47,48]. In general, activation of CB1 receptors by eCBs decreases the probability of release of neurotransmitters through multiple mechanisms, comprising an inhibition of calcium influx and an activation of potassium channels [46,47,48,49]. These effects are terminated by eCB reuptake followed by degradation; 2AG by MAGL pre-synaptically and AEA by FAAH post-synaptically, as mentioned above. Furthermore, a large proportion (45–48%) of synapses in different brain regions are tripartite [47] (Figure 1B), formed by a pre-synaptic neuron, a post-synaptic neuron, and a glial cell, usually an astrocyte, which expresses CB1R [47]. In response to neuronal activation, eCBs are released by the postsynaptic neurons and activate CB1R expressed on astrocytes. The astrocytes respond with an increase in calcium from intracellular stores leading to the release of gliotransmitters (Figure 1B), capable of modulating the presynaptic and postsynaptic circuit elements [47,50,51]. Through these mechanisms eCBs
