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Cell type–specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs

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.

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Figure 1: Generation of D1R–DARPP-32/Flag and D2R–DARPP-32/Myc mice.
Figure 2: Experimental design and tagged DARPP-32 immunoprecipitation.
Figure 3: Effects of D1R and D2R agonists on DARPP-32 phosphorylation in striatal slices.
Figure 4: Effects of D1R and D2R agonists on DARPP-32 phosphorylation in vivo.
Figure 5: Differential regulation of DARPP-32 phosphorylation by psychostimulants and antipsychotics.

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Acknowledgements

This work was funded by US National Institutes of Health grants MH074866 and DA10044, the Picower Foundation, the Simons Foundation, the Peter J. Sharp Foundation, US Department of Health and Human Services Administration on Aging grant 90AZ2791 and Department of Defense/US Army Medical Research Acquisition Activity grants DAMD17-02-1-0705 and W81XWH-05-1-0146.

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Correspondence to Paul Greengard.

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Bateup, H., Svenningsson, P., Kuroiwa, M. et al. Cell type–specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. Nat Neurosci 11, 932–939 (2008). https://doi.org/10.1038/nn.2153

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