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The Journal of Neuroscience, July 25, 2007, 27(30):8011-8022; doi:10.1523/JNEUROSCI.2079-07.2007
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Neurobiology of Disease
Serotonin Neuron Transplants Exacerbate L-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease
Thomas Carlsson,1 Manolo Carta,1,2 Christian Winkler,3 Anders Björklund,2 andDeniz Kirik1 1CNS Disease Modeling Unit and 2Neurobiology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden, and 3Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
Correspondence should be addressed to Deniz Kirik, Wallenberg Neuroscience Center, BMC A11, 221 84 Lund, Sweden. Email: deniz.kirik{at}med.lu.se
Clinical trials in patients with Parkinson's disease have shown that transplants of fetal mesencephalic dopamine neurons can form a new functional innervation of the host striatum, but the clinical benefits have been highly variable: some patients have shown substantial recovery in motor function, whereas others have shown no improvement and even a worsening in the 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinetic side effects. Differences in the composition of the grafted cell preparation may contribute to these discrepancies. In particular, the number of serotonin neurons contained in the graft can vary greatly depending on the dissection of the fetal tissue. Importantly, serotonin neurons have the ability to store and release dopamine, formed from exogenously administered L-DOPA. Here, we have evaluated the effect of transplants containing serotonin neurons, or a mixture of dopamine and serotonin neurons, on L-DOPA-induced dyskinesias in 6-hydroxydopamine-lesioned animals. As expected, dopamine neuron-rich grafts induced functional recovery, accompanied by a 60% reduction in L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks. Rats with serotonin-rich grafts with few dopamine neurons, in contrast, showed a progressive worsening of their L-DOPA-induced dyskinesias over time, and no functional improvement. The antidyskinetic effect of dopamine-rich grafts was independent of the number of serotonin neurons present. We conclude that serotonin neurons in the grafts are likely to have a detrimental effect on L-DOPA-induced dyskinesias in cases in which the grafts contain no or few dopamine neurons.
Key words: 5-hydroxytryptamine; 6-hydroxydopamine; cell grafting; dopamine; levodopa; ventral mesenchephalon
Received May 7, 2007; revised June 9, 2007; accepted June 13, 2007.
Correspondence should be addressed to Deniz Kirik, Wallenberg Neuroscience Center, BMC A11, 221 84 Lund, Sweden. Email: deniz.kirik{at}med.lu.se
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