According to the adenosine hypothesis of schizophrenia, the classically associated hyperdopaminergic state may be secondary to a loss of function of the adenosinergic system. Such a hypoadenosinergic state might either be due to a reduction of the extracellular levels of adenosine or alterations in the density of adenosine A receptors (ARs) or their degree of functional heteromerization with dopamine D receptors (DR). In the present study, we provide preclinical and clinical evidences for this latter mechanism. Two animal models for the study of schizophrenia endophenotypes, namely the phencyclidine (PCP) mouse model and the AR knockout mice, were used to establish correlations between behavioural and molecular studies. In addition, a new AlphaLISA-based method was implemented to detect native AR-DR heteromers in mouse and human brain. First, we observed a reduction of prepulse inhibition in AR knockout mice, similar to that observed in the PCP animal model of sensory gating impairment of schizophrenia, as well as a significant upregulation of striatal DR without changes in AR expression in PCP-treated animals. In addition, PCP-treated animals showed a significant reduction of striatal AR-DR heteromers, as demonstrated by the AlphaLISA-based method. A significant and pronounced reduction of AR-DR heteromers was next demonstrated in postmortem caudate nucleus from schizophrenic subjects, even though both DR and AR were upregulated. Finally, in PCP-treated animals, sub-chronic administration of haloperidol or clozapine counteracted the reduction of striatal AR-DR heteromers. The degree of AR-DR heteromer formation in schizophrenia might constitute a hallmark of the illness, which indeed should be further studied to establish possible correlations with chronic antipsychotic treatments.