Endocannabinoids are known to influence synaptic plasticity, and are in particular thought to mediate long-term depression (LTD, which refers to neuronal firing, not psychological depression). Short-term depression (STD) has also been described (see the next paragraph). First reported in the striatum, this system is known to function in several other brain structures such as the nucleus accumbens, amygdala, hippocampus, cerebral cortex, cerebellum, ventral tegmental area (VTA), brain stem, and superior colliculus. Typically, these retrograde transmitters are released by the postsynaptic neuron and induce synaptic depression by activating the presynaptic CB1 receptors.
It has further been suggested that different endocannabinoids, i.e., 2-AG and anandamide, might mediate different forms of synaptic depression through different mechanisms. The study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2-AG was found to act on presynaptic CB receptors to mediate retrograde STD following activation of L-type calcium channeles, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced LTD. These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.