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.
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.
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.
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.
Keywords
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Article info
Publication history
Published online: July 15, 2014
Accepted:
July 7,
2014
Received:
April 29,
2014
Identification
Copyright
© 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Unraveling the Mechanism of Dyskinesia One Transcription Factor at a TimeBiological PsychiatryVol. 79Issue 5
- PreviewL-DOPA–induced dyskinesia (LID), or abnormal involuntary movements, is a common side effect of L-DOPA therapy in patients with Parkinson’s disease. When L-DOPA is initially administered, it effectively reverses akinesia caused by the loss of dopamine. However, long-term L-DOPA administration produces a hyperkinetic effect, triggering excessive movements in human patients and in animal models. The mechanisms of LID have been under intense investigation for decades, and numerous important discoveries in the past several years established the key mechanisms of LID development.
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