Elsevier

Neuroscience

Volume 97, Issue 3, May 2000, Pages 505-519
Neuroscience

The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABAA receptor alterations in the human basal ganglia in Huntington's disease

https://doi.org/10.1016/S0306-4522(00)00008-7Get rights and content

Abstract

In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB1, dopamine D1 and D2, adenosine A2a and GABAA receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB1, dopamine D2 and adenosine A2a receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABAA receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB1 receptor binding in the caudate nucleus and putamen; this was associated with a loss of D1 receptors in the caudate nucleus and putamen and a loss of both CB1 and D1 receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB1 receptors and the further depletion of D1 receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABAA receptor binding in the globus pallidus internus.

These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.

Section snippets

Tissue collection

The human brain tissue used in these studies was obtained from the New Zealand Neurological Foundation Human Brain Bank in the Department of Anatomy, University of Auckland and the study was approved by the University of Auckland Human Subjects Ethics Committee.

All control subjects had previously been in good health with no known history of neurological disease or drug treatment and all had died suddenly without the opportunity of receiving any form of medical treatment. For both control and

Results

The principal aim of this study was to investigate the pattern of cannabinoid CB1, dopamine D1 and D2, adenosine A2a and GABAA receptor changes in the basal ganglia in the human brain in early (grade 0), intermediate (grade 1, 2) and late (grade 3) neuropathological grades of Huntington's disease in order to gain further information on the possible neuronal co-localization of these receptors in the human basal ganglia and on the sequence and pattern of neurodegeneration in Huntington's disease.

Discussion

It is now well established that medium spiny neurons of the caudate nucleus and putamen are preferentially vulnerable in Huntington's disease.27 Furthermore, the subset of the medium spiny projection neurons containing GABA/enk demonstrate preferential dysfunction in terminal areas in the GPe.49., 52., 61. In contrast, medium spiny neurons containing GABA/substance P projecting to the GPi are more resistant to dysfunction in early Huntington's disease. However, conflicting information on the

Acknowledgments

This study was supported by grants from the Health Research Council of New Zealand, the New Zealand Neurological Foundation and the New Zealand Lottery Board. Michelle Glass was supported by the J. B. Miller Postgraduate Scholarship from the New Zealand Neurological Foundation Inc.

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