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Presynaptic mechanisms in L-DOPA-induced dyskinesia

Lindgren, Hanna LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2009:25.
Abstract
This study has investigated the impact of presynaptic factors on the development of dyskinesia during chronic L-DOPA treatment in a rat model of Parkinson’s disease (PD). The mechanisms causing dyskinesia are not completely understood but have been proposed to involve changes in gene and protein expression in striatal neurons, which are the main target of dopamine (DA) projections from the substantia nigra pars compacta (SNpc). It has recently become evident that also factors presynaptic of the striatal neurons can contribute to the pathophysiology of dyskinesia. Indeed, abnormally large increases in extracellular DA concentrations have recently been documented in both animal models of PD and human patients following treatment with L-DOPA.... (More)
This study has investigated the impact of presynaptic factors on the development of dyskinesia during chronic L-DOPA treatment in a rat model of Parkinson’s disease (PD). The mechanisms causing dyskinesia are not completely understood but have been proposed to involve changes in gene and protein expression in striatal neurons, which are the main target of dopamine (DA) projections from the substantia nigra pars compacta (SNpc). It has recently become evident that also factors presynaptic of the striatal neurons can contribute to the pathophysiology of dyskinesia. Indeed, abnormally large increases in extracellular DA concentrations have recently been documented in both animal models of PD and human patients following treatment with L-DOPA. The mechanisms underlying such increases have not been resolved. This thesis work has addressed two factors that may determine large surges of extracellular DA upon treatment with L-DOPA, namely angiogenic activity in the microvessels of the basal ganglia and DA release from serotonin (5-HT) neurons.

This thesis demonstrate that dyskinetic rats display a pronounced endothelial proliferation in the basal ganglia, this being most pronounced in the substantia nigra pars reticulata (SNr) and entopeduncular nucleus (EP), where it is associated with an increase in blood-vessel length. Endothelial proliferation is accompanied by increased expression of nestin (an immature endothelial marker) and a downregulation of endothelial barrier antigen (EBA) on blood vessel walls. Moreover, the angiogenic activity seen in dyskinetic rats after L-DOPA-treatment can be attributed to dyskinesiogenic dopamine (D)1-receptor stimulation and is not caused by increased motor activity per se. In contrast, D2-receptor stimulation by L-DOPA appears to limit the extent of this angiogenic response to L-DOPA.

Dopamine release after peripheral administration of L-DOPA was assessed using the microdialysis technique. This thesis shows that dyskinetic rats display a larger surge of striatal and nigral extracellular dopamine (DA) than non-dyskinetic rats, not explainable by differences in L-DOPA levels, DA formation or DA metabolism. Interestingly, dyskinetic rats show higher striatal levels of 5-HT and its metabolite in both the extracellular fluid and in tissue samples, findings indicative of a denser 5-HT innervation. When co-treated with L-DOPA and agonists of the 5-HT-autoreceptors, dyskinetic animals show a blunted surge of extracellular DA along with an attenuation of abnormal involuntary movements. Infusion of tetrodotoxin, a sodium channel blocker, in combination with the 5-HT-autoreceptor agonists does not further reduce the levels of DA in neither striatum nor SNr. These findings strongly suggest that impulse-dependent release from serotonergic neurons is the major contributor to the rise in striatal and nigral extracellular DA seen in dyskinetic animals.

The findings from this thesis have implications for understanding the pathophysiology of the basal ganglia in PD and for evaluating novel treatments. Drugs that can stabilise the microvasculature and/or reduce DA release from 5-HT neurons may provide useful strategies to reduce the motor complications associated with standard L-DOPA pharmacotherapy in PD. (Less)
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author
supervisor
opponent
  • Prof. Hirsch, Etienne, INSERM, experimental Neurol & Therapeutics, Paris
organization
publishing date
type
Thesis
publication status
published
subject
keywords
angiogenesis, dyskinesia, 5-HT, DA, Parkinson's disease, 6-OHDA, microdialysis
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2009:25
pages
172 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
Segerfalksalen, BMC A10
defense date
2009-03-20 09:15
ISSN
1652-8220
ISBN
978-91-86253-12-7
language
English
LU publication?
yes
id
82d6999a-c9af-4e9a-a5bd-5475ffcf7ede (old id 1359439)
date added to LUP
2009-03-16 09:56:08
date last changed
2016-09-19 08:44:51
@phdthesis{82d6999a-c9af-4e9a-a5bd-5475ffcf7ede,
  abstract     = {This study has investigated the impact of presynaptic factors on the development of dyskinesia during chronic L-DOPA treatment in a rat model of Parkinson’s disease (PD). The mechanisms causing dyskinesia are not completely understood but have been proposed to involve changes in gene and protein expression in striatal neurons, which are the main target of dopamine (DA) projections from the substantia nigra pars compacta (SNpc). It has recently become evident that also factors presynaptic of the striatal neurons can contribute to the pathophysiology of dyskinesia. Indeed, abnormally large increases in extracellular DA concentrations have recently been documented in both animal models of PD and human patients following treatment with L-DOPA. The mechanisms underlying such increases have not been resolved. This thesis work has addressed two factors that may determine large surges of extracellular DA upon treatment with L-DOPA, namely angiogenic activity in the microvessels of the basal ganglia and DA release from serotonin (5-HT) neurons. <br/><br>
This thesis demonstrate that dyskinetic rats display a pronounced endothelial proliferation in the basal ganglia, this being most pronounced in the substantia nigra pars reticulata (SNr) and entopeduncular nucleus (EP), where it is associated with an increase in blood-vessel length. Endothelial proliferation is accompanied by increased expression of nestin (an immature endothelial marker) and a downregulation of endothelial barrier antigen (EBA) on blood vessel walls. Moreover, the angiogenic activity seen in dyskinetic rats after L-DOPA-treatment can be attributed to dyskinesiogenic dopamine (D)1-receptor stimulation and is not caused by increased motor activity per se. In contrast, D2-receptor stimulation by L-DOPA appears to limit the extent of this angiogenic response to L-DOPA. <br/><br>
Dopamine release after peripheral administration of L-DOPA was assessed using the microdialysis technique. This thesis shows that dyskinetic rats display a larger surge of striatal and nigral extracellular dopamine (DA) than non-dyskinetic rats, not explainable by differences in L-DOPA levels, DA formation or DA metabolism. Interestingly, dyskinetic rats show higher striatal levels of 5-HT and its metabolite in both the extracellular fluid and in tissue samples, findings indicative of a denser 5-HT innervation. When co-treated with L-DOPA and agonists of the 5-HT-autoreceptors, dyskinetic animals show a blunted surge of extracellular DA along with an attenuation of abnormal involuntary movements. Infusion of tetrodotoxin, a sodium channel blocker, in combination with the 5-HT-autoreceptor agonists does not further reduce the levels of DA in neither striatum nor SNr. These findings strongly suggest that impulse-dependent release from serotonergic neurons is the major contributor to the rise in striatal and nigral extracellular DA seen in dyskinetic animals. <br/><br>
The findings from this thesis have implications for understanding the pathophysiology of the basal ganglia in PD and for evaluating novel treatments. Drugs that can stabilise the microvasculature and/or reduce DA release from 5-HT neurons may provide useful strategies to reduce the motor complications associated with standard L-DOPA pharmacotherapy in PD.},
  author       = {Lindgren, Hanna},
  isbn         = {978-91-86253-12-7},
  issn         = {1652-8220},
  keyword      = {angiogenesis,dyskinesia,5-HT,DA,Parkinson's disease,6-OHDA,microdialysis},
  language     = {eng},
  pages        = {172},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Presynaptic mechanisms in L-DOPA-induced dyskinesia},
  volume       = {2009:25},
  year         = {2009},
}