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Striatal Inhibition of PKA Prevents Levodopa-Induced Behavioural and Molecular Changes in the Hemiparkinsonian Rat

Striatal Inhibition of PKA Prevents Levodopa-Induced Behavioural and Molecular Changes in the Hemiparkinsonian Rat

Manon Lebel, Laure Chagniel, Geneviève Bureau, Michel Cyr

Neurobiol Dis. 2010 Apr;38(1):59-67.

PMID: 20060905

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1421654	L-3,4-Dihydroxyphenylalanine methyl ester hydrochloride		1421-65-4	Price

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