Dopamine D-1 receptor-induced gene transcription is modulated by DARPP-32

The role of the dopamine- and cyclic AMP-regulated phosphoprotein of M-r 32 ,000 (DARPP-32) in dopaminergic regulation of gene transcription in striatu m and globus pallidus was examined. Mice with targeted disruption of the ge ne encoding DARPP-32, its homologue, inhibitor-1, or both, were used. Pharm acological characterization showed that mutant mice had normal basal levels of dopamine D-1 and D-2 receptors and adenosine A(2A) receptors. Basal exp ression levels of the striatonigral-specific neuropeptides substance P and prodynorphin and the immediate early genes c-fos and NGFI-A were also unalt ered in mutant mice. A full D-1 receptor agonist, SKF 82958, up-regulated t he expression of these neuropeptides and immediate early genes significantl y more in wild-type mice than in mice lacking DARPP-32. Moreover, the addit ive stimulation of SKF 82958 and quinelorane, a D-2 receptor agonist, on c- fos mRNA in globus pallidus was significantly decreased in DARPP-32 and DAR PP-32/I-1 knockout mice. No changes in dopamine receptor-induced gene expre ssion were found in I-1 knockout mice. These results demonstrate an importa nt involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and i n pallidal neurons, which do not contain DARPP-32.