title: D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model.
abstract: Dopamine released by amphetamine decreases the in vivo binding of PET radioligands to the dopamine D(2) receptor. Although concentrations of extracellular dopamine largely return to baseline within 1 to 2 h after amphetamine treatment, radioligand binding remains decreased for several hours. The purpose of this study was to determine whether the prolonged decrease of radioligand binding after amphetamine administration is caused by receptor internalization. To distinguish dopamine displacement from receptor internalization, we used wild-type and arrestin3 (arr3) knockout mice, which are incapable of internalizing D(2) receptors. In addition, we used both the D(2) selective agonist [(11)C]MNPA (which is thought to bind to the high affinity state of the receptor) and the D(2) selective antagonist [(18)F]fallypride (which does not differentiate between high and low affinity state). After an initial baseline scan, animals were divided in three groups for a second scan: either 30 min or 4 h after amphetamine administration (3 mg/kg, i.p.) or as retest. At 30 min, [(11)C]MNPA showed greater displacement than [(18)F]fallypride, but each radioligand gave similar displacement in knockout and wild-type mice. At 4 h, the binding of both radioligands returned to baseline in arr3 knockout mice, but remained decreased in wild-type mice. Radioligand binding was unaltered on retest scanning. Our results suggest that the prolonged decrease of radioligand binding after amphetamine is mainly due to internalization of the D(2) receptor rather than dopamine displacement. In addition, this study demonstrates the utility of small animal PET to study receptor trafficking in vivo in genetically modified mice.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Mette
authors.initials: M
authors.lastname: Skinbjerg
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Shuiyu
authors.initials: S
authors.lastname: Lu
authors.forename: Annika
authors.initials: A
authors.lastname: Thorsell
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D002462:Cell Membrane / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D005260:Female; D005462:Fluorine Radioisotopes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009288:Naproxen / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019390:Arrestins; D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; C082333:arrestin3; D009288:Naproxen; D000661:Amphetamine