A significant subpopulation of neurons in rat nucleus accumbens (NAc) coexpress dopamine D1 and D2 receptors， which can form a D1-D2 receptor complex， but their relevance in addiction is not known. The existence of the D1-D2 heteromer in the striatum of rat and monkey was established using PLA， FRET and co-immunoprecipitation. In rat， D1-D2 receptor heteromer activation led to place aversion and abolished cocaine CPP and locomotor sensitization， cocaine intravenous self-administration and reinstatement of cocaine seeking， as well as inhibited sucrose preference and abolished the motivation to seek palatable food. Selective disruption of this heteromer by a specific interfering peptide induced reward-like effects and enhanced the above cocaine-induced effects， including at a subthreshold dose of cocaine. The D1-D2 heteromer activated Cdk5/Thr75-DARPP-32 and attenuated cocaine-induced pERK and ΔFosB accumulation， together with inhibition of cocaine-enhanced local field potentials in NAc， blocking thus the signaling pathway activated by cocaine: D1R/cAMP/PKA/Thr34-DARPP-32/pERK with ΔFosB accumulation. In conclusion， our results show that the D1-D2 heteromer exerted tonic inhibitory control of basal natural and cocaine reward， and therefore initiates a fundamental physiologic function that limits the liability to develop cocaine addiction.