期刊
JOURNAL OF PARKINSONS DISEASE
卷 10, 期 4, 页码 1503-1514出版社
IOS PRESS
DOI: 10.3233/JPD-202061
关键词
6-OHDA; BDNF; dyskinesia; D3 receptors; Parkinson's disease
资金
- Italian Ministry of Education, Universities and Research, Progetto di Ricerca di Interesse Nazionale (PRIN) [2010-AHHP5H]
Background: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. Objective: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D-1 receptor agonists. Methods: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D-1 and D-3 receptors expression levels and D-1 receptor-dependent signaling pathways were measured in the striatum. Results: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D-3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D-1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D-1-D-3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. Conclusion: Here we provide evidence for a functional link between BDNF, D-3 receptors and D-1-D-3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D-1-D-3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.
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