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The Journal of Neuroscience, July 9, 2008, 28(28):7113-7120; doi:10.1523/JNEUROSCI.3952-07.2008

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Neurobiology of Disease
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

Charles R. Gerfen,¹ Ronald Paletzki,¹ and Paul Worley²

¹Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, and ²Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Charles R. Gerfen, Building 111, National Institutes of Health Animal Center, Dickerson, MD 20842. Email: gerfenc{at}mail.nih.gov

Dopamine receptor signaling exhibits prominent plasticity that is important for the pathogenesis of both addictive and movement disorders. Psychoactive stimulants that activate the dopamine D₁ 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.

Key words: amphetamine; basal ganglia; D₁; dopamine; dopamine receptor; drug abuse; Parkinson's disease; striatum

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Received March 23, 2007; revised Feb. 27, 2008; accepted May 20, 2008.

Correspondence should be addressed to Charles R. Gerfen, Building 111, National Institutes of Health Animal Center, Dickerson, MD 20842. Email: gerfenc{at}mail.nih.gov

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