Abstract
l-3,4-dihydroxyphenylalanine methyl ester hydrochloride (l-DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of abnormal involuntary movements (AIMS) known as l-DOPA-induced dyskinesias (LID). The molecular changes underlying LID are not completely understood. Using the 6-hydroxydopamine-lesioned rat model of PD, we showed that l-DOPA elicits profound alterations in the activity of three LID molecular markers, namely DeltaFosB, dopamine, cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as in phosphorylation levels of the cytoskeletal-associated protein tau. These modifications are triggered by protein kinase A (PKA) activation and intermittent stimulation of dopamine receptors as they are totally prevented by intrastriatal injections of Rp-cAMPS, a PKA inhibitor, or by continuous administration of l-DOPA via subcutaneous mini-pump. Importantly, Rp-cAMPS does not modulate the positive effect of l-DOPA on locomotor deficits and significantly attenuates the emergence of AIMS in 6-hydroxydopamine hydrobromide-lesioned rats. Even if decreased PKA signalling in the striatum may represent a clinical challenge, these data provide novel evidence that PKA activation, through modification of striatal signalling and alterations of cytoskeletal constituents, plays a key role in the manifestation of LID.
Copyright 2009 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Behavior, Animal / physiology
-
Biomarkers / metabolism
-
Corpus Striatum / drug effects
-
Corpus Striatum / metabolism*
-
Corpus Striatum / physiopathology
-
Cyclic AMP / analogs & derivatives
-
Cyclic AMP / pharmacology
-
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
-
Cyclic AMP-Dependent Protein Kinases / metabolism*
-
Disease Models, Animal
-
Dopamine / metabolism
-
Dopamine and cAMP-Regulated Phosphoprotein 32 / drug effects
-
Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
-
Dyskinesia, Drug-Induced / metabolism*
-
Dyskinesia, Drug-Induced / physiopathology
-
Enzyme Inhibitors / pharmacology
-
Extracellular Signal-Regulated MAP Kinases / drug effects
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Gait Disorders, Neurologic / drug therapy
-
Gait Disorders, Neurologic / metabolism
-
Gait Disorders, Neurologic / physiopathology
-
Infusion Pumps, Implantable
-
Levodopa / adverse effects
-
Levodopa / antagonists & inhibitors*
-
Locomotion / drug effects
-
Locomotion / physiology
-
Male
-
Parkinsonian Disorders / drug therapy*
-
Parkinsonian Disorders / metabolism*
-
Parkinsonian Disorders / physiopathology
-
Proto-Oncogene Proteins c-fos / drug effects
-
Proto-Oncogene Proteins c-fos / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Signal Transduction / drug effects
-
Signal Transduction / physiology
-
Thionucleotides / pharmacology
Substances
-
Biomarkers
-
Dopamine and cAMP-Regulated Phosphoprotein 32
-
Enzyme Inhibitors
-
Fosb protein, rat
-
Ppp1r1b protein, rat
-
Proto-Oncogene Proteins c-fos
-
Thionucleotides
-
adenosine-3',5'-cyclic phosphorothioate
-
Levodopa
-
Cyclic AMP
-
Cyclic AMP-Dependent Protein Kinases
-
Extracellular Signal-Regulated MAP Kinases
-
Dopamine