Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 28, Pages 7113-7120Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3952-07.2008
Keywords
amphetamine; basal ganglia; D-1; dopamine; dopamine receptor; drug abuse; Parkinson's disease; striatum
Categories
Funding
- Intramural NIH HHS [Z99 MH999999, Z01 MH002497-18] Funding Source: Medline
- NIDA NIH HHS [R01 DA011742, R01 DA011742-08, R37 DA010309, DA11742] Funding Source: Medline
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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.
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