Details

Autor(en) / Beteiligte

• Bastide, Matthieu F
• de la Crompe, Brice
• Doudnikoff, Evelyne
• Fernagut, Pierre-Olivier
• Gross, Christian E
• Mallet, Nicolas
• Boraud, Thomas
• Bézard, Erwan

Titel

Inhibiting Lateral Habenula Improves L-DOPA–Induced Dyskinesia

Ist Teil von

• Biological psychiatry (1969), 2016-03, Vol.79 (5), p.345-353

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Abstract Background A systematic search of brain nuclei putatively involved in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson’s disease shed light, notably, upon the lateral habenula (LHb), which displayed an overexpression of the ∆FosB, ARC, and Zif268 immediate-early genes only in rats experiencing abnormal involuntary movements (AIMs). We thus hypothesized that LHb might play a role in LID. Methods ∆FosB immunoreactivity, 2-deoxyglucose uptake, and firing activity of LHb were studied in experimental models of Parkinson’s disease and LID. ΔFosB-expressing LHb neurons were then targeted using the Daun02-inactivation method. A total of 18 monkeys and 55 rats were used. Results LHb was found to be metabolically modified in dyskinetic monkeys and its neuronal firing frequency significantly increased in ON L-DOPA dyskinetic 6-hydroxydopamine-lesioned rats, suggesting that increased LHb neuronal activity in response to L-DOPA is related to AIM manifestation. Therefore, to mechanistically test if LHb neuronal activity might affect AIM severity, following induction of AIMs, 6-hydroxydopamine rats were injected with Daun02 in the LHb previously transfected with ß-galactosidase under control of the FosB promoter. Three days after Daun02 administration, animals were tested daily with L-DOPA to assess LID and L-DOPA–induced rotations. Inactivation of ∆FosB-expressing neurons significantly reduced AIM severity and also increased rotations. Interestingly, the dopaminergic D1 receptor was overexpressed only on the lesioned side of dyskinetic rats in LHb and co-localized with ΔFosB, suggesting a D1 receptor-mediated mechanism supporting the LHb involvement in AIMs. Conclusions This study highlights the role of LHb in LID, offering a new target to innovative treatments of LID.