Stimulation of either class II metabotropic glutamate receptors (mGluRs) or A1 adenosine receptors, both of which are negatively coupled to adenylate cyclase, led to a transient synaptic depression, but when coupled with a simultaneous increase in [cGMP], elicited robust presynaptic long-term synaptic depression that persisted for more than 2 hours [25]. This evidence concerns the gene ADORA1 and major depressive disorder.