Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experim...

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Published in:Biological psychiatry (1969) Vol. 65; no. 6; pp. 518 - 526
Main Authors: Schuster, Stefan, Doudnikoff, Evelyne, Rylander, Daniella, Berthet, Amandine, Aubert, Incarnation, Ittrich, Carina, Bloch, Bertrand, Cenci, M. Angela, Surmeier, D. James, Hengerer, Bastian, Bezard, Erwan
Format: Journal Article
Language:English
Published: New York, NY Elsevier 15.03.2009
Subjects:
Adult and adolescent clinical studies
Animals
Basic Medicine
Biological and medical sciences
Calcium Channel Blockers - administration & dosage
Calcium Channel Blockers - pharmacology
Calcium Channels, L-Type - drug effects
Cerebrum - metabolism
Cerebrum - ultrastructure
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dendritic Spines - drug effects
Dendritic Spines - ultrastructure
Disease Models, Animal
Dose-Response Relationship, Drug
Dyskinesia, Drug-Induced - metabolism
Dyskinesia, Drug-Induced - prevention & control
Enkephalins - metabolism
Isradipine - administration & dosage
Isradipine - pharmacology
Isradipine - therapeutic use
Levodopa - adverse effects
Levodopa - pharmacology
Male
Medical and Health Sciences
Medical sciences
Medicin och hälsovetenskap
Medicinska och farmaceutiska grundvetenskaper
Motor Activity - drug effects
Nervous system (semeiology, syndromes)
Nervous system as a whole
Neurology
Neurosciences
Neurovetenskaper
Nimodipine - pharmacology
Organic mental disorders. Neuropsychology
Oxidopamine
Protein Precursors - metabolism
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Rats
Rats, Wistar
RNA, Messenger - metabolism
Sympatholytics - administration & dosage
Animal model
Parkinson's disease
Rat
Calcium antagonist
Parkinson disease
Cognition
Abnormal movement
Involuntary movement
Development
Dihydropyridine derivatives
Degenerative disease
Neurological disorder
Motricity
Dyskinesia
Nervous system diseases
Rodentia
Electron microscopy
Antiparkinson agent
Motor control
Cerebral disorder
Anatomic pathology
Vertebrata
Mammalia
Neuron
Aminoacid
Animal
Central nervous system disease
medium spiny neurons
L-type calcium channel
Dopa
Isradipine
Extrapyramidal syndrome
ISSN:0006-3223, 1873-2402, 1873-2402
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Summary:Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.
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content type line 23
ISSN:0006-3223
1873-2402
1873-2402
DOI:10.1016/j.biopsych.2008.09.008