Dopamine receptor and transporter levels are altered in the brain of Purkinje Cell Degeneration mutant mice

Abstract

The Purkinje Cell Degeneration (Nna1pcd, pcd) mutant mouse is mainly characterized by the complete, primary loss of the Purkinje cells and the secondary, partial, retrograde loss of the granule and inferior olive neurons and is considered a model of human degenerative ataxia. We determined, by in vitro quantitative autoradiography and in situ hybridization, the effects of the Purkinje cell deprivation on the dopaminergic system of the Nna1pcd mutant mouse. The dopamine transporters, as determined by [3H]WIN35428 binding, were increased compared with wild-type mice in the ventral mesencephalic dopaminergic nuclei and in the lateral striatum, motor cortex and septum. In the cerebellum of Nna1pcd mice, the dopamine transporters showed a significant increase in the deep cerebellar nuclei, but were significantly decreased in the molecular layer. The D1-like receptors, as determined by [3H]SCH23390 binding, increased significantly in the Nna1pcd substantia nigra. The D2/D3 receptors, as determined by [3H]raclopride binding, exhibited a significant decrease in lateral divisions of the striatum. Significant increases in D2-like receptors, as determined by [3H]nemonapride binding, were observed in most divisions of the striatum as well as in septum, hippocampus, and piriform cortex. This D2-like fraction most probably corresponds to the D4 receptor subtype. In the cerebellum of Nna1pcd mice, D2-like receptors were significantly decreased in the molecular layer. The results suggest an increased excitatory input on the dopaminergic mesencephalic neurons and an alteration of the dopaminergic neurotransmission in basal ganglia, cortical and limbic regions of the Nna1pcd mutant mouse. In the cerebellum, the significant downregulation of the dopamine transporters and D2-like receptors in the mutant cerebellar molecular layer is possibly due to the absence of the Purkinje cells.