Although the mechanisms underlying striatal neurodegeneration are poorly 
understood, we have shown that striatal pathogenesis may be initiated by high 
synaptic levels of extracellular dopamine (DA). Here we investigated in rat 
striatal primary neurons the mobilization of the mitogen-activated protein 
kinase (MAPK) signaling pathways after treatment with DA. Instead of observing 
an elevation of the archetypical pro-cytotoxic MAPKs, p-JNK and p-p38 MAPK, we 
found that DA, acting through D1 DA receptors, induced a sustained stimulation 
of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via 
a cAMP/protein kinase A (PKA)/Rap1/B-Raf / MAPK/ERK kinase (MEK) pathway. 
Blockade of D2 DA receptors, beta-adrenergic receptors or N-methyl-D-aspartate 
receptors with receptor-specific antagonists had no significant effect on this 
process. Activation of D1 DA receptors and PKA by DA caused phosphorylation and 
inactivation of the striatal-enriched tyrosine phosphatase, an important 
phosphatase for the dephosphorylation and subsequent inactivation of p-ERK in 
the striatum. Interestingly, p-ERK was primarily retained in the cytoplasm, with 
only low amounts translocated to the nucleus. The scaffold protein 
beta-arrestin2 interacted with both p-ERK and D1 DA receptor, triggering the 
cytosolic retention of p-ERK and inducing striatal neuronal apoptotic death. 
These data provide unique insight into a novel role of p-ERK in striatal 
neurodegeneration.