Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization in vivo with PET/fMRI

This study investigated the dynamics of dopamine receptor desensitization and internalization, thereby proposing a new technique for non-invasive, in vivo measurements of receptor adaptations. The D2/D3 agonist quinpirole, which induces receptor internalization in vitro, was administered at graded doses in a non-human primate model while imaging with simultaneous PET and fMRI. A pronounced temporal divergence between receptor occupancy and fMRI signal was observed: Occupancy remained elevated while fMRI responded transiently. Analogous experiments with an antagonist (prochlorperazine) and a lower-affinity agonist (ropinirole) exhibited reduced temporal dissociation between occupancy and function, consistent with a mechanism of desensitization and internalization that depends upon drug efficacy and affinity. To describe the data, we postulate a model that incorporates internalization into the neurovascular-coupling relationship. This model yielded in vivo desensitization/internalization rates (0.2 min(-1) for quinpirole) consistent with published in vitro measurements. Overall, these results suggest that simultaneous PET/fMRI enables characterization of dynamic neuroreceptor adaptations in vivo, and may offer a first non-invasive method for assessing receptor desensitization and internalization.Neuropsychopharmacology accepted article preview online, 21 September 2015. doi:10.1038/npp.2015.296.