부산대학교 도서관

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. We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1receptor agonists. 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, D1and D3receptors expression levels and D1receptor-dependent signaling pathways were measured in the striatum. BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1–D3receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. Here we provide evidence for a functional link between BDNF, D3receptors and D1–D3receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1–D3receptors 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.