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The Journal of Neuroscience, March 1, 2000, 20(5):1849-1857

Activation of Extracellular Signal-Regulated Protein Kinases Is Associated with a Sensitized Locomotor Response to D₂ Dopamine Receptor Stimulation in Unilateral 6-Hydroxydopamine-Lesioned Rats

Guoping Cai, Xuechu Zhen, Kunihiro Uryu, and Eitan Friedman

Laboratory of Molecular Pharmacology, Department of Pharmacology and Physiology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania 19129

Evidence indicates that mitogen-activated protein kinase (MAPK) pathways play a crucial role in the neurobiology of the nervous system. In the present study, dopamine receptor-mediated regulation of extracellular signal-regulated kinases (ERKs) was examined in rats in which the nigrostriatal dopaminergic pathway was unilaterally lesioned by 6-hydroxydopamine (6-OHDA). Subcutaneous injections of the D₂ receptor agonist quinpirole significantly increased tyrosine-phosphorylated ERK1/2 in lesioned striatum, whereas the D₁ receptor agonist SKF38393 failed to activate ERKs. Quinpirole-induced phosphorylation of ERK1/2 was seen as early as 3 min and peaked at 15 min after the challenge. In parallel, striatal ERK kinase activity, measured by the in vitro kinase assay, was increased 2.5-fold on the lesioned side after the administration of quinpirole. Immunohistochemical examination of brain sections after quinpirole administration revealed significant increases in ERK1/2 immunostaining in perinuclear and intranuclear areas of striatal neurons. This increase was much more pronounced on the lesioned than the intact side. Furthermore, quinpirole-induced contralateral rotation was decreased by 48.7 and 50.7%, respectively, when the striatal ERK pathway was selectively inhibited by a single intrastriatal injection of the MAPK/ERK kinase inhibitor PD098059 or after a continuous 7 d intrastriatal infusion of ERK1/2 antisense oligodeoxynucleotide. The results demonstrate, for the first time, that the ERK signaling pathway is activated in denervated striatum in response to stimulation of D₂ dopamine receptors and that the resulting imbalance in striatal ERK activity contributes, at least in part, to neuronal plasticity that underlies D₂ dopamine receptor-mediated contralateral rotation in unilateral 6-OHDA denervated rats.

Key words: Dopamine receptor; supersensitivity; ERK pathway; locomotion; phosphorylation; striatum

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2051849-09$05.00/0

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