FIGURE 5.

Endocannabinoid retrograde signaling. In the brain, CB1R are mainly located on presynaptic axon terminals, where their activation hyperpolarizes the terminal and decreases neurotransmitter release. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the primary endogenous ligands of CBR. AEA is a partial CB1R agonist, while 2-AG is a full CB1R agonist. eCBs are synthetized by postsynaptic neurons “on demand”, i.e., in response to heightened neuronal activity and increased intracellular Ca²⁺ concentrations. They diffuse through the postsynaptic membrane to the synaptic cleft, travel backward, and activate CB1R at the presynaptic terminals of adjacent neurons, suppressing neurotransmitter release through the short-term plasticity forms: depolarization-induced suppression of inhibition (DSI) at GABAergic synapses and depolarization-induced suppression of excitation (DSE) at glutamatergic synapses (Alger, 2002; Wilson and Nicoll, 2002; Melis, 2004). Created with BioRender.com.