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_2A receptors (A_2ARs) or their degree of functional heteromerization with dopamine D₂ receptors (D₂R). 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 A_2AR knockout mice, were used to establish correlations between behavioural and molecular studies. In addition, a new AlphaLISA-based method was implemented to detect native A_2AR-D₂R heteromers in mouse and human brain. First, we observed a reduction of prepulse inhibition in A_2AR 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 D₂R without changes in A_2AR expression in PCP-treated animals. In addition, PCP-treated animals showed a significant reduction of striatal A_2AR-D₂R heteromers, as demonstrated by the AlphaLISA-based method. A significant and pronounced reduction of A_2AR-D₂R heteromers was next demonstrated in postmortem caudate nucleus from schizophrenic subjects, even though both D₂R and A_2AR were upregulated. Finally, in PCP-treated animals, sub-chronic administration of haloperidol or clozapine counteracted the reduction of striatal A_2AR-D₂R heteromers. The degree of A_2AR-D₂R 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.

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