title: Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia.
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.
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Matthieu F
authors.initials: MF
authors.lastname: Bastide
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Brice
authors.initials: B
authors.lastname: de la Crompe
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Doudnikoff
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France; Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Gross
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mallet
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boraud
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France. Electronic address: erwan.bezard@u-bordeaux.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bézard
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D004594:Electrophysiology; D005260:Female; D017781:Genes, Immediate-Early; D019262:Habenula / Q000187:drug effects*; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D008297:Male; D016627:Oxidopamine / Q000008:administration & dosage; D010300:Parkinson Disease / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C576267:N-(4''-(galactopyranosyl)-3''-nitrobenzyloxycarbonyl)daunomycin; D007980:Levodopa; D016627:Oxidopamine; D003847:Deoxyglucose; D003630:Daunorubicin
keywords: 2-Deoxyglucose; Daun02; Electrophysiology; Macaque; Parkinson’s disease; Rat