Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia. 2016

Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.

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.

UI MeSH Term Description Entries
D007980 Levodopa The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. L-Dopa,3-Hydroxy-L-tyrosine,Dopaflex,Dopar,L-3,4-Dihydroxyphenylalanine,Larodopa,Levopa,3 Hydroxy L tyrosine,L 3,4 Dihydroxyphenylalanine,L Dopa
D008252 Macaca fascicularis A species of the genus MACACA which typically lives near the coast in tidal creeks and mangrove swamps primarily on the islands of the Malay peninsula. Burmese Long-Tailed Macaque,Crab-Eating Monkey,Cynomolgus Monkey,M. f. aurea,M. fascicularis,Macaca fascicularis aurea,Monkey, Crab-Eating,Monkey, Cynomolgus,Crab-Eating Macaque,Burmese Long Tailed Macaque,Crab Eating Macaque,Crab Eating Monkey,Crab-Eating Macaques,Crab-Eating Monkeys,Cynomolgus Monkeys,Long-Tailed Macaque, Burmese,Macaque, Burmese Long-Tailed,Macaque, Crab-Eating,Monkey, Crab Eating
D008297 Male Males
D010300 Parkinson Disease A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75) Idiopathic Parkinson Disease,Lewy Body Parkinson Disease,Paralysis Agitans,Primary Parkinsonism,Idiopathic Parkinson's Disease,Lewy Body Parkinson's Disease,Parkinson Disease, Idiopathic,Parkinson's Disease,Parkinson's Disease, Idiopathic,Parkinson's Disease, Lewy Body,Parkinsonism, Primary
D003342 Corpus Striatum Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE. Lenticular Nucleus,Lentiform Nucleus,Lentiform Nuclei,Nucleus Lentiformis,Lentiformis, Nucleus,Nuclei, Lentiform,Nucleus, Lenticular,Nucleus, Lentiform,Striatum, Corpus
D003630 Daunorubicin A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS. Daunomycin,Rubidomycin,Rubomycin,Cerubidine,Dauno-Rubidomycine,Daunoblastin,Daunoblastine,Daunorubicin Hydrochloride,NSC-82151,Dauno Rubidomycine,Hydrochloride, Daunorubicin,NSC 82151,NSC82151
D003847 Deoxyglucose 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. 2-Deoxy-D-glucose,2-Deoxyglucose,2-Desoxy-D-glucose,2 Deoxy D glucose,2 Deoxyglucose,2 Desoxy D glucose
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004409 Dyskinesia, Drug-Induced Abnormal movements, including HYPERKINESIS; HYPOKINESIA; TREMOR; and DYSTONIA, associated with the use of certain medications or drugs. Muscles of the face, trunk, neck, and extremities are most commonly affected. Tardive dyskinesia refers to abnormal hyperkinetic movements of the muscles of the face, tongue, and neck associated with the use of neuroleptic agents (see ANTIPSYCHOTIC AGENTS). (Adams et al., Principles of Neurology, 6th ed, p1199) Dyskinesia, Medication-Induced,Medication-Induced Dyskinesia,Drug-Induced Dyskinesia,Drug-Induced Dyskinesias,Dyskinesia, Drug Induced,Dyskinesia, Medication Induced,Dyskinesias, Drug-Induced,Dyskinesias, Medication-Induced,Medication Induced Dyskinesia,Medication-Induced Dyskinesias
D004594 Electrophysiology The study of the generation and behavior of electrical charges in living organisms particularly the nervous system and the effects of electricity on living organisms.

Related Publications

Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
January 2002, Revue neurologique,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
January 2001, Clinical neuropharmacology,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
May 2001, MMW Fortschritte der Medizin,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
January 2005, Clinical neuropharmacology,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
March 1972, No to shinkei = Brain and nerve,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
June 1973, Rinsho shinkeigaku = Clinical neurology,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
September 2008, Nature reviews. Neuroscience,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
January 2017, Translational neurodegeneration,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
January 2015, Bulletin de l'Academie nationale de medecine,
Matthieu F Bastide, and Brice de la Crompe, and Evelyne Doudnikoff, and Pierre-Olivier Fernagut, and Christian E Gross, and Nicolas Mallet, and Thomas Boraud, and Erwan Bézard
January 2011, International review of neurobiology,
Copied contents to your clipboard!