Measure striatal adenosine-dopamine receptors interactions: from molecule to behaviors

Massachusetts General Hospital, Boston MA

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Abstract

Project Summary / Abstract Adenosine 2A receptors (A2AR) and dopamine D2 receptors (D2R) are G-protein coupled receptors (GPCRs) that are highly colocalized in the striatum. A2AR and D2R form functional heterodimers that exert allosteric antagonism on the other receptor. Based on ample in vitro and in vivo animal evidence, several hypotheses have proposed the critical involvement of A2AR-D2R heterodimer in dopamine-associated disorders, such as psychosis and schizophrenia. For example, a recent adenosine hypothesis of schizophrenia posts that a reduced tonic level of adenosine control through A2AR-D2R heterodimers contributes to an elevated dopaminergic function in schizophrenia. However, mechanistic studies investigating the role of A2AR-D2R heterodimers in patients remain limited, primarily due to the scarcity of evidence demonstrating antagonistic interactions between A2AR-D2R heterodimers in human subjects. To address these limitations, noninvasive neuroimaging tools can potentially measure the dynamic interactions of A2AR-D2R heterodimers in vivo. Hence, the proposed study aims to provide neuroimaging data to demonstrate the bilateral interactions between A2AR and D2R in nonhuman primates using pharmacological challenges. Specifically, we will administer a D2R antagonist (cold raclopride) or an A2AR antagonist (caffeine) to measure the drug-induced changes of receptor binding at the A2AR and D2R, respectively, using [18F]MNI-444 and [11C]Raclopride PET. These findings will provide quantitative results indicating the level of receptor occupancy required to modulate the other receptor system. Furthermore, we aim to translate the imaging paradigm into human subjects to investigate the impacts of modulating D2R by an A2AR antagonist (caffeine) on behaviors. We will use [11C]Raclopride PET/fMRI to measure the simultaneous responses in D2/D3R binding and the reward learning behaviors with and without oral caffeine. The successful execution of these experiments will not only demonstrate the ability of PET/MRI to characterize receptor-receptor interactions in vivo but also provide translational evidence supporting the functional existence of A2AR-D2R heterodimers in human subjects. These findings will lay the foundation for future clinical research to test novel adenosine-based hypotheses in psychiatric disorders.