A primate model of Huntington's disease: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon

doi:10.1016/0014-4886(90)90014-J

Experimental Neurology

Volume 108, Issue 2, May 1990, Pages 91-104

https://doi.org/10.1016/0014-4886(90)90014-J Get rights and content

Abstract

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.

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Citation Excerpt :
In view of the complex assessments and the duration of our working hypothesis, it was ethically unacceptable to perform full lesions of both caudate and putamen bilaterally. The chosen lesion paradigm builds on the existing literature on the ability of unilateral putaminal lesions to generate motor deficits (Hantraye et al., 1990) and provides novel proof of concept of the effect of bilateral caudate lesions on cognition. Indeed, the strength of the work presented here is the in depth characterization of changes in cognitive performance and capacity to retain previously learnt rules, and the ability of lesioned NHPs to learn new rules after bilateral QA administration to the caudate nuclei.
As research progresses in the understanding of the molecular and cellular mechanisms underlying neurodegenerative diseases like Huntington's disease (HD) and expands towards preclinical work for the development of new therapies, highly relevant animal models are increasingly needed to test new hypotheses and to validate new therapeutic approaches. In this light, we characterized an excitotoxic lesion model of striatal dysfunction in non-human primates (NHPs) using cognitive and motor behaviour assessment as well as functional imaging and post-mortem anatomical analyses.
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A primate model of Huntington's disease: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon

Abstract

Brain Res.

Brain Res.

Neuroscience

Neuroscience

Brain Res.

Brain Res.

Neuroscience

Neuroscience

Neuroscience

Prog. Brain Res.

J. Neurol. Sci.

Neurosci. Lett.

Brain Res.

Brain Res.

Trends Neurosci.

Neuroscience

Neurosci. Lett.

Brain Res.

Prog. Neurobiol.

Exp. Neurol.

Lancet

Somatostatin is increased in the basal ganglia in Huntington's disease

Ann. Neurol.

Comparison of ketamine with the combination of ketamine and xylazine for effective anesthesia in the rhesus monkey (macaca mulata)

Lab. Anim. Sci.

Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid

Nature (London)

Excitotoxin lesions do not mimic the alteration of somatostatin in Huntington's disease

Brain Res.

Positron emission tomographic scan investigations of Huntington's disease: Cerebral metabolic correlates of cognitive function

Ann. Neurol.

Chemical pathology of Huntington's disease

Annu. Rev. Pharmacol. Toxicol.

Catecholminergic brain stem regulatory systems

Huntington's chorea: Current neuropathological status

Differentiation of the dopamine mechanisms mediating stereotyped behavior and hyperactivity in the nucleus accumbens and caudate-putamen

J. Pharm. Pharmacol.

The use of excitatory amino acids as selective neurotoxins