Behavioral and morphological comparison of two nonhuman primate models of Huntington's disease.
OBJECTIVE
Huntington's disease is a progressive neurodegenerative disease characterized by movement disorder, cognitive deterioration, and selective striatal degeneration. No effective treatment exists, and thus stable primate models could aid in the development of novel therapies.


METHODS
Two primate models of Huntington's disease were analyzed: bilateral stereotactic intrastriatal injections of quinolinic acid (QA), and daily systemic intramuscular administration of 3-nitropropionic acid (3-NP) for up to 8 weeks in male Cebus apella monkeys. The animals' behavior was evaluated before, during, and 3 months after administration of the neurotoxin. Magnetic resonance imaging scans of the brain were obtained before and after treatment.


RESULTS
Frontal cognitive function as evaluated by object retrieval-detour task test demonstrated a marked deterioration in successful responses, with an increase in barrier reaches in both groups. No significant change in performance of fine motor tasks was observed. QA-treated animals displayed hyperactivity at night. Animals in both groups demonstrated abnormal posture, and the 3-NP-treated group showed spontaneous and apomorphine-induced dystonia and dyskinesia. The QA-treated group displayed large areas of increased signal on T2-weighted images in the caudate and putamen bilaterally. Treatment with 3-NP resulted in smaller lesions. Immunohistochemistry and morphometric analyses revealed that both groups had lesions in the striatum. A large area of neuronal loss with glial sparing was observed in the QA-treated group, including the caudate and putamen bilaterally. The 3-NP-treated group displayed smaller lesions restricted to the dorsolateral putamen.


CONCLUSIONS
These results suggest that both QA and 3-NP induce behavioral and morphological features that resemble the juvenile and akinetic-rigid variants of Huntington's disease, with the group with 3-NP-induced lesions displaying smaller lesions and spontaneous dyskinesia.
Roitberg
Ben Zion
BZ
Department of Neurosurgery, University of Illinois, 912 S. Wood Street, M/C 799, Chicago, IL 60612, USA. roitberg@uic.edu
Emborg
Marina E
ME
Sramek
Joseph G
JG
Palfi
Stephane
S
Kordower
Jeffrey H
JH
D000818:Animals; D001931:Brain Mapping; D002421:Caudate Nucleus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002428:Cebus; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006816:Huntington Disease / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007267:Injections; D007273:Injections, Intramuscular; D008279:Magnetic Resonance Imaging; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009574:Nitro Compounds; D011340:Problem Solving / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000633:toxicity*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011699:Putamen / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D017378:Quinolinic Acid / Q000633:toxicity*
D009574:Nitro Compounds; D011422:Propionates; D017378:Quinolinic Acid; C015392:3-nitropropionic acid