If the spontaneous co-release of glutamate and acetylcholine acting on metabotropic glutamate receptors (mGluRs) or muscarinic receptors resulted in a state of presynaptic depression, then MOR-mediated inhibition of spontaneous neurotransmission could relieve this presynaptic depression and augment release of glutamate. Here, OPRM1 is linked to major depressive disorder.