Interestingly, M1 activation exerts opposite effects on endocannabinoid release at excitatory and inhibitory synapses. At glutamatergic synapses, M1 activation tonically inhibits endocannabinoid release through suppressing the opening of Cav1.3 channels, whereas at inhibitory synapses, M1 receptor activation promotes endocannabinoid release and thus suppresses inhibitory synaptic transmission. This difference may be attributed to differences in subcellular localization of M1 receptor. Excitatory synapses in MSNs are formed mostly on spines and inhibitory synapses are primarily located on dendritic shafts and soma [47,48,49]. The M1-CB1 mediated excitatory effect requires functional interaction between Cav1.3 and scaffolding proteins Shank and Homer, which are enriched in spines [28]. However, M1-mediated suppression of inhibitory transmission more likely is caused by direct enhancement of production of endocannabinoids at inhibitory synapses through Gq, PLCβ signaling by M1 receptor activation.
