Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors.
BACKGROUND
We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA).


METHODS
6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/DeltaFosB expression were examined immunohistochemically.


RESULTS
L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/DeltaFosB.


CONCLUSIONS
L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment.
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Sweden.
Jenny E
JE
Westin
Linda
L
Vercammen
Elissa M
EM
Strome
Christine
C
Konradi
M Angela
MA
Cenci
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002452:Cell Count; D003714:Denervation; D015259:Dopamine Agents; D018492:Dopamine Antagonists / Q000494:pharmacology; D004399:Dynorphins / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D004745:Enkephalins / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007980:Levodopa; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology*; D017072:Neostriatum / Q000033:anatomy & histology* / Q000201:enzymology*; D009476:Neurons, Efferent / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004745:Enkephalins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D004399:Dynorphins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3