The striatal dopamine D₂ receptor (D₂R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D₂R are highly expressed in the striatum, where they form heteromers with the adenosine A_2A receptor (A_2AR). Changes in the density of A_2AR-D₂R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A₂R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A_2AR-D₂R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A_2AR-D₂R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A_2AR-D₂R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D₂R, inducing a clash with A_2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D₂R that enhances the interaction with A_2AR. It is proposed that an increase in A_2AR-D₂R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A_2AR-D₂R heteromerization can explain its low EPS liability.