Striatal inhibition of PKA prevents levodopa-induced behavioural and molecular changes in the hemiparkinsonian rat

Neurobiol Dis. 2010 Apr;38(1):59-67. doi: 10.1016/j.nbd.2009.12.027. Epub 2010 Jan 11.

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.

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