Article abstract
Nature Neuroscience 11, 932 - 939 (2008)
Published online: 11 July 2008 | doi:10.1038/nn.2153
Cell type–specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs
Helen S Bateup1, Per Svenningsson1,2, Mahomi Kuroiwa3, Shiaoching Gong4,5, Akinori Nishi1,3, Nathaniel Heintz4,5 & Paul Greengard1
Abstract
DARPP-32 is a dual-function protein kinase/phosphatase inhibitor that is involved in striatal signaling. The phosphorylation of DARPP-32 at threonine 34 is essential for mediating the effects of both psychostimulant and antipsychotic drugs; however, these drugs are known to have opposing behavioral and clinical effects. We hypothesized that these drugs exert differential effects on striatonigral and striatopallidal neurons, which comprise distinct output pathways of the basal ganglia. To directly test this idea, we developed bacterial artificial chromosome transgenic mice that allowed the analysis of DARPP-32 phosphorylation selectively in striatonigral and striatopallidal neurons. Using this new methodology, we found that cocaine, a psychostimulant, and haloperidol, a sedation-producing antipsychotic, exert differential effects on DARPP-32 phosphorylation in the two neuronal populations that can explain their opposing behavioral effects. Furthermore, we found that a variety of drugs that target the striatum have cell type–specific effects that previous methods were not able to discern.
- Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA.
- Center for Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz vag 2, Stockholm 171 77, Sweden.
- Department of Pharmacology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
- Laboratory of Molecular Biology, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA.
- GENSAT project, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA.
Correspondence to: Paul Greengard1 e-mail: greengard@rockefeller.edu
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