6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death.

The 6-hydroxydopamine (6-OHDA) model of nigral injury in rats has been in use as a standard animal model of parkinsonism for many years. While earlier studies established the time course for loss of catecholamine histofluorescence or tyrosine hydroxylase immunostaining in the cell bodies and terminals, these alterations in phenotypic expression do not define the time course of morphologic degeneration. We have therefore used a silver impregnation method to characterize the time course and morphology of the degeneration of neurons in the nigrostriatal system. Abundant neuronal death was observed in substantia nigra pars compacta (SNpc) as early as 12 hours after nigral 6-OHDA injection, and prior to any evidence of striatal terminal degeneration. From 1 to 7 days neuron death was accompanied by striatal fibre degeneration. After 7 days, fibre degeneration was no longer seen, but identifiable neuron death continued at low levels for as long as 31 days, and stained amorphous material was present at 60 days. The morphologic pattern of cell death in the early phase was similar to that in the late phase, and included cytoplasmic silver deposits and dark staining of the nucleolus. At no time was the morphology of apoptosis observed. We conclude that neuron death is a progressive process following 6-OHDA lesion, with similar morphology throughout the course of degeneration.