Deficits in striatal dopamine D-2 receptors and energy metabolism detectedby in vivo MicroPET imaging in a rat model of Huntington's disease

Functional imaging by repeated noninvasive scans of specific F-18 tracer di stribution 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- [F-18]fluoro-D-glucose uptake, was compromised severely 1 week after intras triatal excitotoxin injections. When the same rats were imaged 5 and 7 week s 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'-F-18]fluoroethyl) spip erone binding apparent 1 week postlesion followed by a decline 5 and 7 week s thereafter. Additional experiments revealed that marked upregulation of d opamine D-2 receptors consequent to quinolinic acid injections could be det ected as early as 3 days after the initial insult. Postmortem markers of st riatal GABAergic neurons were assessed in the same rats 7 weeks after the l esion: expression of glutamic acid decarboxylase and dopamine D-1 receptor mRNA, as well as [H-3]SCH-23,390 and [H-3]spiperone binding to dopamine D-1 and D-2 receptors, respectively, detected prominent decrements consequent to the lesion. In contrast, by 7 weeks postlesion [H-3]WIN-35,428 binding t o dopamine transport sites within the striatum appeared to be enhanced prox imal to the quinolinic acid injection sites. The results demonstrate that f unctional imaging using the microPET is a useful technique to explore not o nly the progressive neurodegeneration that occurs in response to excitotoxi c insults, but also to examine more closely the intricacies of neurotransmi tter activity in a small animal model of HD. (C) 2000 Academic Press.