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 A_2a and GABA_A 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 A_2a receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA_A 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 GABA_A 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.