Drug addiction is a psychiatric disorder defined as a compulsive pattern of drug-seeking/taking behaviors, with recurrent episodes of abstinence and relapse. Addictive drugs increase dopamine in the nucleus accumbens (NAc), where it persistently shapes excitatory glutamate transmission, thereby hijacking natural reward processing. Recently, we provide evidence, from mice to humans, that psychostimulants and opiates alter DA-glutamate signal integration in the NAc through a drug-evoked heteromerization (i.e direct physical interaction) of glutamate NMDA receptors (NMDAR) with D1R or D2R. Using temporally-controlled inhibition of D1R-NMDAR heteromerization, we show their selective implication in early phases of cocaine-evoked, whereas preventing D2R-NMDAR heteromerization blocked the persistence of these adaptations.Notably, interfering with these receptor heteromers spared natural reward processing. Because the high prevalence of comorbidities between addiction and mood disorders suggests that brain dysfunctions underlying drug addiction and other psychiatric disorders may rely on partly shared mechanisms, we asked whether receptor heteromerization in the NAc could constitute a common molecular switch in addiction and depression. Using the chronic defeat stress paradigm as a preclinical model of depression, we indeed found that mice developing depressive-like behavior, but not resilient mice, exhibit an increased dopamine-glutamate receptor heteromerization, which blockade fully prevents the onset and persistence of depressive-like symptoms.These findings contribute to a better understanding of common molecular mechanisms underlying addiction and depression and uncover dopamine-glutamate heteromer as targets with potential therapeutic value for multiple psychiatric diseases associated with alterations in dopamine and glutamate-dependent transmissions.