Deficits in striatal dopamine D(2) receptors and energy metabolism detected by in vivo microPET imaging in a rat model of Huntington's disease.
Functional imaging by repeated noninvasive scans of specific (18)F tracer distribution using a high-resolution small-animal PET scanner, the microPET, assessed the time course of alterations in energy utilization and dopamine receptors in rats with unilateral striatal quinolinic acid lesions. Energy utilization ipsilateral to the lesion, determined using scans of 2-deoxy-2-[(18)F]fluoro-d-glucose uptake, was compromised severely 1 week after intrastriatal excitotoxin injections. When the same rats were imaged 5 and 7 weeks postlesion, decrements in energy metabolism were even more prominent. In contrast, lesion-induced effects on dopamine D(2) receptor binding were more progressive, with an initial upregulation of [3-(2'-(18)F]fluoroethyl)spiperone binding apparent 1 week postlesion followed by a decline 5 and 7 weeks thereafter. Additional experiments revealed that marked upregulation of dopamine D(2) receptors consequent to quinolinic acid injections could be detected as early as 3 days after the initial insult. Postmortem markers of striatal GABAergic neurons were assessed in the same rats 7 weeks after the lesion: expression of glutamic acid decarboxylase and dopamine D(1) receptor mRNA, as well as [(3)H]SCH-23,390 and [(3)H]spiperone binding to dopamine D(1) and D(2) receptors, respectively, detected prominent decrements consequent to the lesion. In contrast, by 7 weeks postlesion [(3)H]WIN-35,428 binding to dopamine transport sites within the striatum appeared to be enhanced proximal to the quinolinic acid injection sites. The results demonstrate that functional imaging using the microPET is a useful technique to explore not only the progressive neurodegeneration that occurs in response to excitotoxic insults, but also to examine more closely the intricacies of neurotransmitter activity in a small animal model of HD.
Araujo
D M
DM
Department of Medical and Molecular Pharmacology, Crump Institute for Biological Imaging, Los Angeles, California, 90095, USA.
Cherry
S R
SR
Tatsukawa
K J
KJ
Toyokuni
T
T
Kornblum
H I
HI
D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D019788:Fluorodeoxyglucose F18; D005968:Glutamate Decarboxylase / Q000235:genetics; D006816:Huntington Disease / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism*; D017403:In Situ Hybridization; D009410:Nerve Degeneration / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism / Q000494:pharmacology; D013378:Substantia Nigra / Q000378:metabolism; D014055:Tomography, Emission-Computed / Q000379:methods*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D009498:Neurotoxins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019788:Fluorodeoxyglucose F18; D014316:Tritium; D013134:Spiperone; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid; D003042:Cocaine