Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia.
Biological Psychiatry. 2016-03-01; 79(5): 345-353
DOI: 10.1016/j.biopsych.2014.08.022
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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.