AbstractAlthough 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, β‐adrenergic receptors orN‐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 β‐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.