title: Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization In Vivo with PET/fMRI.
abstract: 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 non-human primates while imaging with simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (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. We postulated a model that incorporates internalization into a neurovascular-coupling relationship. This model yielded in vivo desensitization/internalization rates (0.2/min 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.
authors.affiliation: A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Christin Y
authors.initials: CY
authors.lastname: Sander
authors.affiliation: A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.affiliation: A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Ciprian
authors.initials: C
authors.lastname: Catana
authors.affiliation: A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.|Harvard Medical School, Boston, MA, USA.|Health Sciences and Technology, Harvard-MIT, Cambridge, MA, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rosen
authors.affiliation: A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Mandeville
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D018491:Dopamine Agonists / Q000008:administration & dosage*; D018492:Dopamine Antagonists / Q000008:administration & dosage; D065127:Dopamine D2 Receptor Antagonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000008:administration & dosage; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008959:Models, Neurological; D049268:Positron-Emission Tomography / Q000379:methods*; D011346:Prochlorperazine / Q000008:administration & dosage; D019257:Quinpirole / Q000008:administration & dosage*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C046649:ropinirole; D019257:Quinpirole; D011346:Prochlorperazine