D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model.
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.
Skinbjerg
Mette
M
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
Liow
Jeih-San
JS
Seneca
Nicholas
N
Hong
Jinsoo
J
Lu
Shuiyu
S
Thorsell
Annika
A
Heilig
Markus
M
Pike
Victor W
VW
Halldin
Christer
C
Sibley
David R
DR
Innis
Robert B
RB
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
D019390:Arrestins; D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; C082333:arrestin3; D009288:Naproxen; D000661:Amphetamine