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J Pharmacol Exp Ther. 2014 Nov;351(2):440-7. doi: 10.1124/jpet.114.218966. Epub 2014 Sep 11.

Chronic L-dopa decreases serotonin neurons in a subregion of the dorsal raphe nucleus.

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Department of Neurosciences, University of Toledo College of Medicine, Toledo, Ohio.
Department of Neurosciences, University of Toledo College of Medicine, Toledo, Ohio


L-Dopa (l-3,4-dihydroxyphenylalanine) is the precursor to dopamine and has become the mainstay therapeutic treatment for Parkinson's disease. Chronic L-dopa is administered to recover motor function in Parkinson's disease patients. However, drug efficacy decreases over time, and debilitating side effects occur, such as dyskinesia and mood disturbances. The therapeutic effect and some of the side effects of L-dopa have been credited to its effect on serotonin (5-HT) neurons. Given these findings, it was hypothesized that chronic L-dopa treatment decreases 5-HT neurons in the dorsal raphe nucleus (DRN) and the content of 5-HT in forebrain regions in a manner that is mediated by oxidative stress. Rats were treated chronically with l-dopa (6 mg/kg; twice daily) for 10 days. Results indicated that the number of 5-HT neurons was significantly decreased in the DRN after l-dopa treatment compared with vehicle. This effect was more pronounced in the caudal-extent of the dorsal DRN, a subregion found to have a significantly higher increase in the 3,4-dihydroxyphenylacetic acid/dopamine ratio in response to acute L-dopa treatment. Furthermore, pretreatment with ascorbic acid (400 mg/kg) or deprenyl (2 mg/kg) prevented the l-dopa-induced decreases in 5-HT neurons. In addition, 5-HT content was decreased significantly in the DRN and prefrontal cortex by l-dopa treatment, effects that were prevented by ascorbic acid pretreatment. Taken together, these data illustrate that chronic L-dopa causes a 5-HT neuron loss and the depletion of 5-HT content in a subregion of the DRN as well as in the frontal cortex through an oxidative-stress mechanism.

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