Levodopa induction of Fos immunoreactivity in rat brain following partial and complete lesions of the substantia nigra.
It is controversial whether levodopa (L-DOPA) therapy in the early stages of Parkinson's disease (PD) predisposes to later complications. Partial lesions of the substantia nigra (SN) in rat provide a model of the early stages of PD. We have investigated the potential effects of L-DOPA in early PD by analyzing its influence on the activity of the immediate early gene Fos in the partially lesioned rat. Fos has been used to examine neuronal response to a variety of stimuli in vivo, and L-DOPA is known to increase Fos-like immunoreactivity (FosLI) in striatal neurons after complete lesions of the SN. To determine its effects following partial lesions, we analyzed FosLI in rats given L-DOPA after partial (50-90%) and complete (> 90%) unilateral 6-hydroxydopamine lesions of the SN. Behavioral responses to intraperitoneal injections of apomorphine and amphetamine during life and cell counts of neurons in the SN with tyrosine hydroxylase-like immunoreactivity established the extent of nigral cell loss. FosLI was present in the striatum on the lesioned side predominantly laterally in rats with partial lesions and throughout in rats with complete lesions. Sections counterstained with toluidine blue revealed that only medium-sized striatal neurons displayed FosLI. Prominent FosLI was also found in the ipsilateral piriform cortex and amygdala in both groups and additionally in the ipsilateral zona incerta in the complete group. Therefore L-DOPA induces Fos in the striatum after partial as well as complete SN lesions. This result suggests that L-DOPA-induced Fos expression may occur in the early stages of PD and may not require dopamine receptor upregulation, which is believed to develop only in completely lesioned rats and in later stages of PD. The unexpected induction of Fos activity in brain regions besides the striatum suggests that L-DOPA therapy in patients with PD may have more widespread effects than previously anticipated. Since Fos is known to regulate gene transcription, potential alterations in its activity may contribute to the complications associated with L-DOPA therapy in PD.
Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown 02129.
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Cole
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Growdon
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000473:pathology*
D016760:Proto-Oncogene Proteins c-fos; D007980:Levodopa; D016627:Oxidopamine