Variable effects of chronic subcutaneous administration of rotenone on striatal histology

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Abstract
When infused in rats, rotenone, a mitochondrial complex I inhibitor, induces alterations that resemble the histological changes of Parkinson's disease, particularly degeneration of the nigrostriatal dopaminergic system. However, the specificity of rotenone effects has been challenged recently. We have re‐examined the alterations caused by rotenone in the substantia nigra and the striatum of rats after infusion of rotenone (2 mg/kg per day s.c.) for 21 days. Three patterns of striatal tyrosine‐hydroxylase immunoreactivity (TH‐IR) were observed: 46% of animals showed no reduction, and 46% of animals showed diffuse reduction in TH‐IR, whereas one animal presented a focal loss of TH‐IR in the striatum. Confocal microscopy analysis showed that the vesicular monoamine transporter (VMAT2) was decreased in parallel with TH‐IR, strongly suggesting a loss of striatal DA nerve terminals in animals with diffuse or central TH‐IR loss. However, no significant loss of TH‐IR neurons was observed in the substantia nigra. Analysis of NeuN and DARPP‐32 immunoreactivity, and Nissl staining, in the striatum showed no striatal neuronal loss in animals with either preserved TH‐IR or diffuse TH‐IR reduction. However, in the animal with focal TH‐IR loss, severe neuronal loss was evident in the center and the periphery of the striatum, together with microglial activation detected by OX‐6 and OX‐42 staining. Thus, in most cases, chronic subcutaneous infusion of low doses of rotenone does not induce significant striatal neuronal loss, despite TH‐IR and VMAT‐IR reduction in a subset of animals, supporting the use of rotenone as a model of Parkinson's disease under carefully controlled experimental conditions. J. Comp. Neurol. 478:418–426, 2004.