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Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia.
- Source :
-
Biological psychiatry [Biol Psychiatry] 2016 Mar 01; Vol. 79 (5), pp. 354-361. Date of Electronic Publication: 2014 Jul 15. - Publication Year :
- 2016
-
Abstract
- Background: ΔFosB is a surrogate marker of L-DOPA-induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson's disease L-DOPA long-term treatment. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown.<br />Methods: We used the Daun02 prodrug-inactivation method associated with lentiviral expression of β-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson's disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability.<br />Results: We first show that daunorubicin, the active product of Daun02 metabolism by β-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing β-galactosidase upon D1 dopamine receptor stimulation. We then demonstrate that the selective, and reversible, inhibition of FosB/ΔFosB-expressing striatal neurons with Daun02 decreases the severity of LID while improving the beneficial effect of L-DOPA.<br />Conclusions: These results establish that FosB/ΔFosB accumulation ultimately results in altered neuronal electrical properties sustaining maladaptive circuits leading not only to LID but also to a blunted response to L-DOPA. These findings further reveal that targeting dyskinesia can be achieved without reducing the antiparkinsonian properties of L-DOPA when specifically inhibiting FosB/ΔFosB-accumulating neurons.<br /> (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Daunorubicin administration & dosage
Disease Models, Animal
Macaca fascicularis
Male
Oxidopamine administration & dosage
Patch-Clamp Techniques
Rats
Rats, Sprague-Dawley
Receptors, Dopamine D1 metabolism
Antiparkinson Agents adverse effects
Daunorubicin analogs & derivatives
Dyskinesia, Drug-Induced drug therapy
Levodopa adverse effects
Neostriatum drug effects
Neurons drug effects
Parkinson Disease complications
Proto-Oncogene Proteins c-fos metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2402
- Volume :
- 79
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Biological psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 25146322
- Full Text :
- https://doi.org/10.1016/j.biopsych.2014.07.007