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.
Keywords
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Article info
Publication history
Published online: September 09, 2014
Accepted:
August 29,
2014
Received in revised form:
August 27,
2014
Received:
May 23,
2014
Identification
Copyright
© 2016 Published by Elsevier Inc.
