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Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia.
Neurobiol Dis. 2011 Sep; 43(3):576-87.ND

Abstract

Fetal dopamine (DA) cell transplantation has shown to be efficient in reversing behavioral impairments associated with Parkinson's disease. However, the beneficial effects on motor behavior and L-DOPA-induced dyskinesia have varied greatly in between clinical trials and patients within the same trial. Recently, the inclusion of serotonin (5-HT) neurons in the grafted tissue has been suggested to play an important negative role, in particular, on the effect of L-DOPA-induced dyskinesia. In the present study we have evaluated the influence of different ratios of DA neurons in relation to 5-HT neurons in the graft on spontaneous motor behavior and L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. We show that using the standard dissection method that gives rise to a DA:5-HT ratio in the graft of 2:1 to 1:2 there is significant and consistent improvement in spontaneous motor behavior and reversal of L-DOPA-induced dyskinesia. Increasing the ratio of 5-HT neurons in the graft, to a DA:5-HT ratio of in between 1:3 and 1:10, still induces significant reduction of L-DOPA-induced dyskinesia, suggesting that the detrimental effect of 5-HT neurons on L-DOPA-induced dyskinesia is prevented even by small numbers of DA neurons in the graft. Nonetheless, while the post-synaptic responses were normalized following peripheral L-DOPA delivery in animals with low DA:5-HT ratio, we observed a pharmacological indication of hyperactive pre-synaptic response in these animals. These data suggests that 5-HT cells within a graft are neither detrimental nor beneficial for functional effects of DA-rich transplants; however, in absence of sufficient numbers of DA neurons, the 5-HT neurons may induce negative effects following L-DOPA therapy. In summary, our data indicate that for future clinical trials the inclusion of 5-HT neurons in grafted tissue is not critical as long as there are sufficient numbers of DA cells in the graft.

Authors+Show Affiliations

Department of Neurology, University Hospital Freiburg, 79106 Freiburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21600983

Citation

García, Joanna, et al. "Impact of Dopamine to Serotonin Cell Ratio in Transplants On Behavioral Recovery and L-DOPA-induced Dyskinesia." Neurobiology of Disease, vol. 43, no. 3, 2011, pp. 576-87.
García J, Carlsson T, Döbrössy M, et al. Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia. Neurobiol Dis. 2011;43(3):576-87.
García, J., Carlsson, T., Döbrössy, M., Nikkhah, G., & Winkler, C. (2011). Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia. Neurobiology of Disease, 43(3), 576-87. https://doi.org/10.1016/j.nbd.2011.05.004
García J, et al. Impact of Dopamine to Serotonin Cell Ratio in Transplants On Behavioral Recovery and L-DOPA-induced Dyskinesia. Neurobiol Dis. 2011;43(3):576-87. PubMed PMID: 21600983.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia. AU - García,Joanna, AU - Carlsson,Thomas, AU - Döbrössy,Máté, AU - Nikkhah,Guido, AU - Winkler,Christian, Y1 - 2011/05/13/ PY - 2011/02/23/received PY - 2011/04/30/revised PY - 2011/05/05/accepted PY - 2011/5/24/entrez PY - 2011/5/24/pubmed PY - 2012/5/23/medline SP - 576 EP - 87 JF - Neurobiology of disease JO - Neurobiol Dis VL - 43 IS - 3 N2 - Fetal dopamine (DA) cell transplantation has shown to be efficient in reversing behavioral impairments associated with Parkinson's disease. However, the beneficial effects on motor behavior and L-DOPA-induced dyskinesia have varied greatly in between clinical trials and patients within the same trial. Recently, the inclusion of serotonin (5-HT) neurons in the grafted tissue has been suggested to play an important negative role, in particular, on the effect of L-DOPA-induced dyskinesia. In the present study we have evaluated the influence of different ratios of DA neurons in relation to 5-HT neurons in the graft on spontaneous motor behavior and L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. We show that using the standard dissection method that gives rise to a DA:5-HT ratio in the graft of 2:1 to 1:2 there is significant and consistent improvement in spontaneous motor behavior and reversal of L-DOPA-induced dyskinesia. Increasing the ratio of 5-HT neurons in the graft, to a DA:5-HT ratio of in between 1:3 and 1:10, still induces significant reduction of L-DOPA-induced dyskinesia, suggesting that the detrimental effect of 5-HT neurons on L-DOPA-induced dyskinesia is prevented even by small numbers of DA neurons in the graft. Nonetheless, while the post-synaptic responses were normalized following peripheral L-DOPA delivery in animals with low DA:5-HT ratio, we observed a pharmacological indication of hyperactive pre-synaptic response in these animals. These data suggests that 5-HT cells within a graft are neither detrimental nor beneficial for functional effects of DA-rich transplants; however, in absence of sufficient numbers of DA neurons, the 5-HT neurons may induce negative effects following L-DOPA therapy. In summary, our data indicate that for future clinical trials the inclusion of 5-HT neurons in grafted tissue is not critical as long as there are sufficient numbers of DA cells in the graft. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/21600983/Impact_of_dopamine_to_serotonin_cell_ratio_in_transplants_on_behavioral_recovery_and_L_DOPA_induced_dyskinesia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(11)00158-6 DB - PRIME DP - Unbound Medicine ER -