A primate model of Huntington's disease: behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon.
Unilateral caudate-putamen (CP) lesions induced by the glutamate receptor agonist ibotenic acid in baboons produced a neuropathological and behavioral model of Huntington's disease (HD) in the nonhuman primate. Neuropathological evaluation of the lesioned caudate-putamen revealed a neurodegenerative pattern resembling HD. The ibotenic acid-infused CP areas showed a neuronal loss in Nissl-stained sections and a marked astrocytic gliosis by immunohistochemical staining for glial-fibrillary-acidic protein. Acetylcholinesterase fiber staining was severely reduced in the lesioned CP, while afferent dopaminergic fibers, as shown by tyrosine hydroxylase staining, were relatively spared. There was a moderate reduction of met-enkephalin staining in the globus pallidus-pars lateralis ipsilateral to the ibotenic acid lesion, indicating a partial denervation of this structure following the lesion. In the behavioral studies a dyskinetic syndrome with features in common with HD was provoked in the lesioned animals following dopamine receptor agonist administration (1-2 mg/kg apomorphine). The symptoms included hyperkinesia, chorea, dystonia, postural asymmetries, head, and orofacial dyskinesia. The apomorphine test was highly reproducible and individual animals responded with a similar set and incidence of dyskinesia in successive tests. Since the behavioral observations following excitotoxic caudate-putamen damage parallel symptoms in HD patients given dopamine stimulatory drugs, a hypothesis is presented for the observed abnormal movements suggesting that the CP lesions reduce movement thresholds while the activation of dopaminoceptive regions induces dyskinesias.
Hantraye
P
P
Lira-CNRS Unit 1285, Service Hospitalier Frédéric Joliot, Orsay, France.
Riche
D
D
Maziere
M
M
Isacson
O
O
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology / Q000523:psychology; D002421:Caudate Nucleus / Q000473:pathology; D004195:Disease Models, Animal; D004421:Dystonia / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*; D007051:Ibotenic Acid; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009068:Movement; D010215:Papio; D011699:Putamen / Q000473:pathology
D007051:Ibotenic Acid; D001058:Apomorphine