Differences between dorsal and ventral striatum in Drd1a dopamine receptor coupling of dopamine- and cAMP-regulated phosphoprotein-32 to activation of extracellular signal-regulated kinase.
Dopamine receptor signaling exhibits prominent plasticity that is important for the pathogenesis of both addictive and movement disorders. Psychoactive stimulants that activate the dopamine D(1) receptor (Drd1a) induce the rapid phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in neurons of the nucleus accumbens and ventral striatum. This response is known to be dependent on the phosphatase inhibitor dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) and appears critical for the sensitization of Drd1a responses that contributes to addiction. Loss of dopamine input to the striatum, as in models of Parkinson's disease (PD), also results in a sensitization of responses to dopamine agonists that is manifest by increased activation of ERK1/2 in the dorsal striatum. Here, we test whether DARPP-32 is required for sensitization of Drd1a responses in a PD model. In the normal dorsal striatum, there is minimal Drd1a-mediated activation of ERK1/2; however, in the PD model there is robust Drd1a-mediated activation of ERK1/2. In both wild-type and DARPP-32 knock-out mice, Drd1a robustly induces pERK1/2 throughout the dopamine-depleted striatum. These findings indicate that Drd1a sensitization relevant for PD occurs by a novel mechanism that does not require DARPP-32.
Gerfen
Charles R
CR
Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA. gerfenc@mail.nih.gov
Paletzki
Ronald
R
Worley
Paul
P
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001479:Basal Ganglia; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000172:deficiency / Q000378:metabolism*
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; C497929:Ppp1r1b protein, mouse; D017447:Receptors, Dopamine D1; C098593:dopamine D1A receptor; D049452:Green Fluorescent Proteins; D007980:Levodopa; D000661:Amphetamine; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine