Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia

Biol Psychiatry. 2016 Mar 1;79(5):345-353. doi: 10.1016/j.biopsych.2014.08.022. Epub 2014 Sep 9.


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: 2-Deoxyglucose; Daun02; Electrophysiology; Macaque; Parkinson’s disease; Rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects*
  • Daunorubicin / administration & dosage
  • Daunorubicin / analogs & derivatives*
  • Deoxyglucose / pharmacokinetics
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / drug therapy*
  • Electrophysiology
  • Female
  • Genes, Immediate-Early
  • Habenula / drug effects*
  • Levodopa / adverse effects*
  • Macaca fascicularis
  • Male
  • Oxidopamine / administration & dosage
  • Parkinson Disease / complications*
  • Rats
  • Rats, Sprague-Dawley


  • N-(4''-(galactopyranosyl)-3''-nitrobenzyloxycarbonyl)daunomycin
  • Levodopa
  • Oxidopamine
  • Deoxyglucose
  • Daunorubicin