SSTR5 and CB1R exist as constitutive heterodimers in rat brain regions and cotransfected HEK-293 cells. Concurrent receptor activation leads to preferential disruption of SSTR5/CB1R heterodimer and formation of SSTR5 homodimer. SSTR5 plays the major role in the regulation of cAMP/PKA/ERK1/2 signaling pathways in cotransfected cells. Time course of PI3K phosphorylation is altered upon concurrent receptor activation.