Presynaptic mechanisms in L-DOPA-induced dyskinesia
Author
Summary, in English
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.
Department/s
Publishing year
2009
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2009:25
Document type
Dissertation
Publisher
Department of Experimental Medical Science, Lund Univeristy
Topic
- Neurosciences
Keywords
- angiogenesis
- dyskinesia
- 5-HT
- DA
- Parkinson's disease
- 6-OHDA
- microdialysis
Status
Published
Research group
- Basal Ganglia Pathophysiology
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-86253-12-7
Defence date
20 March 2009
Defence time
09:15
Defence place
Segerfalksalen, BMC A10
Opponent
- Etienne Hirsch (Prof.)