In contrast, CB1 receptors at glutamatergic synapses, suppress excitatory inputs onto the glutamatergic receptors on the DA neurons [57,60,61]. This mechanism involves glutamate release at synapses in prelimbic frontal cortex and in NAc at D1-enriched medium spiny neurons (D1-MSNs) (reviewed in [62]). Activation of the prefrontal glutamate afferents can lead to long-term depression (LTD) of NAc glutamatergic synapses, an effect also involving 2-AG release, presynaptic CB1-receptor and postsynaptic metabotropic glutamate receptor 5 (mGluR5) activation [62,63,64]. Mechanistically (Figure 2B), the activation of mGluR5 by released glutamate leads to the synthesis and release of 2-AG, which then retrogradely activates CB1 receptors to inhibit additional glutamate release (reviewed in [62]). This activation of CB1R by eCBs is usually accompanied by LTD of neurons [65].
