The pattern of neurodegeneration in Huntington's disease: A comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations inthe human basal ganglia in Huntington's disease

In order to investigate the sequence and pattern of neurodegeneration in Hu ntington's disease, the distribution and density of cannabinoid CB1, dopami ne D-1 and D-2, adenosine A(2a) and GABA(A) receptor changes were studied i n the basal ganglia in early (grade 0), intermediate (grades 1, 2) and adva nced (grade 3) neuropathological grades of Huntington's disease. The result s showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the ve ry early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB1, dopamine D-2 and adenosine A(2a) receptor binding in t he caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermed iate neuropathological grades (grades 1, 2) showed a further marked decreas e of CB1 receptor binding in the caudate nucleus and putamen; this was asso ciated with a loss of D-1 receptors in the caudate nucleus and putamen and a loss of both CB1 and D-1 receptors in the substantia nigra. Finally, adva nced grades of Huntington's disease showed an almost total loss of CB1 rece ptors and the further depletion of D-1 receptors in the caudate nucleus, pu tamen and globus pallidus internus, and an increase in GABAA receptor bindi ng in the globus pallidus internus. These findings suggest that there is a sequential but overlapping pattern o f neurodegeneration of GABAergic striatal efferent projection neurons in in creasing neuropathological grades of Huntington's disease. First, GABA/enke phalin striatopallidal neurons projecting to the globus pallidus externus a re 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 striatopa llidal neurons projecting to the globus pallidus internus are affected in t he late grades of the disease. In addition, the finding that cannabinoid re ceptors are dramatically reduced in all regions of the basal ganglia in adv ance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington 's disease. (C) 2000 IBRO. Published by Elsevier Science Ltd.