Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia

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• 作者：Matthieu F. Bastide^a ; ^b ; Brice de la Crompe^a ; ^b ; Evelyne Doudnikoff^a ; ^b ; Pierre-Olivier Fernagut^a ; ^b ; Christian E. Gross^a ; ^b ; ^c ; Nicolas Mallet^a ; ^b ; Thomas Boraud^a ; ^b ; Erwan Bé ; zard^a ; ^b ; ^{erwan.bezard@u-bordeaux.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Daun02 ; 2-Deoxyglucose ; Electrophysiology ; Macaque ; Parkinson&rsquo ; s disease ; Rat
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：79
• 期：5
• 页码：345-353
• 全文大小：1940 K

文摘

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.