D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase

Dopamine effects in the striatum are mediated principally through the D1 and D2 dopamine receptor subtypes, which are segregated to the direct and indirect striatal projection neurons. After degeneration of the nigrostriatal dopamine system, direct pathway neurons display a supersensitive response to D1 do-pamine receptor agonists, which is demonstrated by the induc-tion of immediate early genes (IEGs), such as c-fos. Here we show, using analysis of receptor-mediated signal transduction, including protein phosphorylation and induction of IEGs, that D1 dopamine receptor supersensitivity is attributable to a switch to ERK1/2/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) in direct pathway neu-rons. Normally, in the dopamine-intact striatum, activation of ERK1/2/MAP kinase is shown to be restricted to indirect and not direct pathway neurons in response to stimulation of corti