Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors.

Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA
Biol Psychiatry. 2007 62 (7): 800-10

PMID: 17662258 · PMCID: PMC4205578 · DOI:10.1016/j.biopsych.2006.11.032

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.

MeSH Terms (24)

Animals Benzazepines Cell Count Denervation Dopamine Agents Dopamine Antagonists Dynorphins Dyskinesia, Drug-Induced Enkephalins Enzyme Activation Female Fluorescent Antibody Technique Immunohistochemistry In Situ Hybridization Levodopa Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Neostriatum Neurons, Efferent Phosphorylation Rats Rats, Sprague-Dawley Receptors, Dopamine D1 Receptors, Dopamine D2

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